ORCID Profile
0000-0002-4839-8471
Current Organisation
Queensland University of Technology
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Biochemistry and Cell Biology | Cellular Interactions (incl. Adhesion, Matrix, Cell Wall) | Animal Physiology - Cell | Animal Neurobiology | Protein Targeting And Signal Transduction | Macromolecular and Materials Chemistry not elsewhere classified | Physiology | Receptors and Membrane Biology | Biochemistry and Cell Biology not elsewhere classified | Structural Biology (incl. Macromolecular Modelling) |
ANZSRC Socio-Economic Objective (SEO)
Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Chemical Sciences | Scientific Instruments | Expanding Knowledge in the Information and Computing Sciences | Cancer and Related Disorders | Cancer and related disorders | Expanding Knowledge in Technology
Related Links
Publications
RNF8 is associated with radioresistance, nodal stage and extranodal spread in oral cavity squamous-cell carcinoma
Publisher: AME Publishing Company
Date: 06-2019
Banf1 as a marker of lung cancer cell sensitivity to cisplatin
Publisher: Elsevier BV
Date: 2019
BRCA1 Deficiency Exacerbates Estrogen-Induced DNA Damage and Genomic Instability
Publisher: American Association for Cancer Research (AACR)
Date: 14-05-2014
DOI: 10.1158/0008-5472.CAN-13-2611
Abstract: Germline mutations in BRCA1 predispose carriers to a high incidence of breast and ovarian cancers. BRCA1 functions to maintain genomic stability through critical roles in DNA repair, cell-cycle arrest, and transcriptional control. A major question has been why BRCA1 loss or mutation leads to tumors mainly in estrogen-regulated tissues, given that BRCA1 has essential functions in all cell types. Here, we report that estrogen and estrogen metabolites can cause DNA double-strand breaks (DSB) in estrogen receptor-α–negative breast cells and that BRCA1 is required to repair these DSBs to prevent metabolite-induced genomic instability. We found that BRCA1 also regulates estrogen metabolism and metabolite-mediated DNA damage by repressing the transcription of estrogen-metabolizing enzymes, such as CYP1A1, in breast cells. Finally, we used a knock-in human cell model with a heterozygous BRCA1 pathogenic mutation to show how BRCA1 haploinsufficiency affects these processes. Our findings provide pivotal new insights into why BRCA1 mutation drives the formation of tumors in estrogen-regulated tissues, despite the general role of BRCA1 in DNA repair in all cell types. Cancer Res 74(10) 2773–84. ©2014 AACR.
EV, microvesicles/microRNAs and stem cells in cancer
Publisher: Springer International Publishing
Date: 2018
DOI: 10.1007/978-3-319-74470-4_8
Abstract: The role of extracellular vesicles (EV) in carcinogenesis has become the focus of much research. These microscopic messengers have been found to regulate immune system function, particularly in tumorigenesis, as well as conditioning future metastatic sites for the attachment and growth of tumor tissue. Through an interaction with a range of host tissues, EVs are able to generate a pro-tumor environment that is essential for tumorigenesis. These small nanovesicles are an ideal candidate for a non-invasive indicator of pathogenesis and/or disease progression as they can display in idualized nucleic acid, protein, and lipid expression profiles that are often reflective of disease state, and can be easily detected in bodily fluids, even after extended cryo-storage. Furthermore, the ability of EVs to securely transport signaling molecules and localize to distant tissues suggests these particles may greatly improve the delivery of therapeutic treatments, particularly in cancer. In this chapter, we discuss the role of EV in the identification of new diagnostic and prognostic cancer biomarkers, as well as the development of novel EV-based cancer therapies.
Epigenetics Underpinning DNA Damage Repair
Publisher: Elsevier
Date: 2015
Localization of Contextual and Context Removed Auditory Fear Memory within the Basolateral Amygdala Complex
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.NEUROSCIENCE.2018.12.004
Abstract: Debilitating and persistent fear memories can rapidly form in humans following exposure to traumatic events. Fear memories can also be generated and studied in animals via Pavlovian fear conditioning. The current study was designed to evaluate basolateral amygdala complex (BLC) involvement following the formation of different fear memories (two contextual fear memories and one adjusted auditory fear memory). Fear memories were created in the same context with five 1.0 mA (0.50 s) foot-shocks and, where necessary, five auditory tones (5 kHz, 75 dB, 20 s). The adjusted auditory fear conditioning protocol was employed to remove background contextual fear and produce isolated auditory fear memories. Immunofluorescent labeling was utilized to identify neurons expressing immediate early genes (IEGs). We found the two contextual fear conditioning (CFC) procedures to produce similar levels of fear-related freezing to context. Contextual fear memories produced increases in BLC IEG expression with distinct and separate patterns of expression. These data suggest contextual fear memories created in slightly altered contexts, can produce unique patterns of amygdala activation. The adjusted auditory fear conditioning procedure produced memories to a tone, but not to a context. This group, where no contextual fear was present, had a significant reduction in BLC IEG expression. These data suggest background contextual fear memories, created in standard auditory fear conditioning protocols, contribute significantly to increases in amygdala activation.
7: Normal bronchial epithelial cells exhibit altered cellular behaviour when exposed to lung cancer cells in a co-culture system
Publisher: Elsevier BV
Date: 2017
Elevating CDCA3 Levels Enhances Tyrosine Kinase Inhibitor Sensitivity in TKI-Resistant EGFR Mutant Non-Small-Cell Lung Cancer
Publisher: MDPI AG
Date: 16-09-2021
Abstract: Tyrosine kinase inhibitors (TKIs) are the first-line therapy for non-small-cell lung cancers (NSCLC) that harbour sensitising mutations within the epidermal growth factor receptor (EGFR). However, resistance remains a key issue, with tumour relapse likely to occur. We have previously identified that cell ision cycle-associated protein 3 (CDCA3) is elevated in adenocarcinoma (LUAD) and correlates with sensitivity to platinum-based chemotherapy. Herein, we explored whether CDCA3 levels were associated with EGFR mutant LUAD and TKI response. We demonstrate that in a small-cohort tissue microarray and in vitro LUAD cell line panel, CDCA3 protein levels are elevated in EGFR mutant NSCLC as a result of increased protein stability downstream of receptor tyrosine kinase signalling. Here, CDCA3 protein levels correlated with TKI potency, whereby CDCA3high EGFR mutant NSCLC cells were most sensitive. Consistently, ectopic overexpression or inhibition of casein kinase 2 using CX-4945, which pharmacologically prevents CDCA3 degradation, upregulated CDCA3 levels and the response of T790M(+) H1975 cells and two models of acquired resistance to TKIs. Accordingly, it is possible that strategies to upregulate CDCA3 levels, particularly in CDCA3low tumours or upon the emergence of therapy resistance, might improve the response to EGFR TKIs and benefit patients.
Abstract PO-031: Aldolase A (ALDOA) is required for efficient DNA double-strand break (DSB) repair
Publisher: American Association for Cancer Research (AACR)
Date: 15-04-2021
DOI: 10.1158/1557-3265.RADSCI21-PO-031
Abstract: Introduction: Metabolic reprogramming, known as the Warburg effect, is one of the universal differences between cancer cells and non-cancerous cells. Glucose metabolism and DNA repair are frequently dysregulated in cancer. Metabolic pathways provide cells with nucleic acids and energy required to repair DNA. However, the underlying mechanisms that promote crosstalk between these processes are unknown. ALDOA is a glycolytic enzyme that catalyses the conversion of fructose 1,6-bisphosphate to glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. ALDOA is overexpressed in several types of cancer. In this study, we demonstrate a novel mechanism through which ALDOA directly regulates DSB repair. Methods: ALDOA was depleted from cells using siRNA and single-shot quantitative proteomics were performed. Immunofluorescence was utilized to determine the localization of ALDOA. DSB repair reporter assays were used to measure DSB break repair. Gene expression was quantified by western blot and qPCR. Immunoprecipitations were used to detect protein:protein interactions. Statistical analysis: The experiments were at least n=3, and data are presented as the means ± SEM. Statistical significance was evaluated using Student’s t-test or one-way ANOVA. Results: In order to identify ALDOA-dependent pathways, we performed quantitative mass spectrometry on ALDOA depleted cells. In addition to the expected decrease in glycolysis pathways, we also observed a significant downregulation of DNA repair proteins in ALDOA depleted cells. Further analysis showed that the ALDOA protein responds to DNA damage (IR) and migrates from the cytosol to the nucleus, suggesting that it could be directly involved in DNA damage repair. Slower clearance of γ-H2AX foci (a DSB marker), and decreased clonogenicity following irradiation (IR) treatment were also observed, indicating dysfunctional DNA repair processes. Repair of DSBs is primarily though the NHEJ (non-homologous end-joining) or HR (homologous recombination) -mediated DNA repair pathways. Silencing ALDOA led to a decrease in both NHEJ- and HR-mediated DSB repair efficiency. This disruption was likely due to the significant reduction of both the mRNA and protein of the DNA repair effector kinases, DNA-Dependent Kinase (DNA-PK) and Ataxia and Telangiectasia Mutated (ATM) in ALDOA-depleted cells. In addition to regulating the expression of DNAPK and ATM we also found that ALDOA directly interacted with both kinases, suggesting that it may have a direct role in regulating their function. Here, we define a role for ALDOA in the repair of DNA DSBs, through the regulation of DNA repair effector kinase expression and function. Conclusion: These results identify crosstalk between metabolic and DNA repair pathways and have implications for cancer treatment and tumorigenesis. The role of ALDOA in DNA repair could promote therapeutic resistance in tumors and may be a future therapeutic target to sensitize tumors to DNA-damaging agents such as radiation. Citation Format: Amila Suraweera, Kenneth O’Byrne, Derek Richard, Emma Bolderson, Thais Sobanski. Aldolase A (ALDOA) is required for efficient DNA double-strand break (DSB) repair [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine 2021 Mar 2-3. Philadelphia (PA): AACR Clin Cancer Res 2021 (8_Suppl):Abstract nr PO-031.
A structural analysis of DNA binding by hSSB1 (NABP2/OBFC2B) in solution
Publisher: Oxford University Press (OUP)
Date: 07-07-2016
DOI: 10.1093/NAR/GKW617
Abstract 996: Cold atmospheric plasma therapy selectively targets triple negative breast cancer cells
Publisher: American Association for Cancer Research (AACR)
Date: 07-2021
DOI: 10.1158/1538-7445.AM2021-996
Abstract: Background: Cancer cells notoriously escape radiation therapy, chemotherapy, hormonal therapy, and other anti-cancer therapies. Among various breast cancer subtypes, triple negative breast cancers (TNBCs) are known for their poor clinical outcome and dearth of effective targeted therapies due to the absence of druggable receptors. Cold atmospheric plasma (CAP) holds promise as a cancer-specific treatment agent that selectively kills basal-like/TN breast cancer cells. Method: In this study, we used plasma-activated media (PAM) to capture and store the multi-modal chemical species of CAP, which significantly expands the treatment scope and flexibility of plasma medicine as a clinical therapeutic approach. The PAM was diluted into different doses and cells were treated for 12 or 24 hours. The effects of PAM on cell viability and ROS levels in 9 different cell lines normal cells (MCF-10A and HEK-293T), luminal breast cancer cell lines (MCF-7, T47D, HCC70), and TNBC cell lines (MDA-MB-468, SUM-159PT, SUM-149PT, MDA-MB-231), were assessed. Results: The results showed that TNBC cells were more highly sensitive, in a dose-dependent manner, to PAM treatment. PAM selectively caused apoptosis of TNBC cell lines compared to luminal lines and had little effect on the normal cell lines. It has been hypothesised that the cancer-selective CAP and PAM cytotoxicity is due in part to reactive oxygen (ROS) and nitrogen species (RNS). Constitutive RONS levels, combined with those present in and/or induced by PAM, can combine to push the cells over a cytotoxic threshold. In support of this, we found a tight correlation (R2=0.7502) between the constitutive ROS level of different cell lines used and their response (cell viability) to 100% PAM treatment, and found that ROS levels selectively increased further in the TNBC& luminal& normal cells in response to PAM. We have also identified a strong synergistic molecular partner that further promotes sensitivity and selectivity of PAM for TNBC cells. Conclusion: We demonstrated that treatment with PAM promotes apoptosis n cell lines representing the most aggressive TNBC subtype. This discovery opens new TNBC-selective opportunities for simultaneous inhibition of erse (parallel) cancer development factors through synergistic interactions enabled through plasma activated biochemical media. Citation Format: Peiyu Wang, Renwu Zhou, Rusen Zhou, Jennifer Gunter, Fiona Simpson, Kostya (Ken) Ostrikov, Derek Richard, Xiaofeng Dai, Erik (Rik) Walter Thompson. Cold atmospheric plasma therapy selectively targets triple negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR Cancer Res 2021 (13_Suppl):Abstract nr 996.
Digital Holographic Imaging as a Method for Quantitative, Live Cell Imaging of Drug Response to Novel Targeted Cancer Therapies
Publisher: Springer New York
Date: 2019
DOI: 10.1007/978-1-4939-9769-5_12
Abstract: Digital holographic imaging (DHI) is a noninvasive, live cell imaging technique that enables long-term quantitative visualization of cells in culture. DHI uses phase-shift imaging to monitor and quantify cellular events such as cell ision, cell death, cell migration, and drug responses. In recent years, the application of DHI has expanded from its use in the laboratory to the clinical setting, and currently it is being developed for use in theranostics. Here, we describe the use of the DHI platform HoloMonitorM4 to evaluate the effects of novel, targeted cancer therapies on cell viability and proliferation using the HeLa cancer cell line as a model. We present single cell tracking and population-wide analysis of multiple cell morphology parameters.
Antiproton induced DNA damage: proton like in flight, carbon-ion like near rest
Publisher: Springer Science and Business Media LLC
Date: 03-05-2013
DOI: 10.1038/SREP01770
COMMD1, from the Repair of DNA Double Strand Breaks, to a Novel Anti-Cancer Therapeutic Target
Publisher: MDPI AG
Date: 16-02-2021
Abstract: Lung cancer has the highest incidence and mortality among all cancers, with non-small cell lung cancer (NSCLC) accounting for 85–90% of all lung cancers. Here we investigated the function of COMMD1 in the repair of DNA double strand breaks (DSBs) and as a prognostic and therapeutic target in NSCLC. COMMD1 function in DSB repair was investigated using reporter assays in COMMD1-siRNA-depleted cells. The role of COMMD1 in NSCLC was investigated using bioinformatic analysis, qRT-PCR and immunoblotting of control and NSCLC cells, tissue microarrays, cell viability and cell cycle experiments. DNA repair assays demonstrated that COMMD1 is required for the efficient repair of DSBs and reporter assays showed that COMMD1 functions in both non-homologous-end-joining and homologous recombination. Bioinformatic analysis showed that COMMD1 is upregulated in NSCLC, with high levels of COMMD1 associated with poor patient prognosis. COMMD1 mRNA and protein were upregulated across a panel of NSCLC cell lines and siRNA-mediated depletion of COMMD1 decreased cell proliferation and reduced cell viability of NSCLC, with enhanced death after exposure to DNA damaging-agents. Bioinformatic analyses demonstrated that COMMD1 levels positively correlate with the gene ontology DNA repair gene set enrichment signature in NSCLC. Taken together, COMMD1 functions in DSB repair, is a prognostic maker in NSCLC and is potentially a novel anti-cancer therapeutic target for NSCLC.
Néstor-Guillermo Progeria Syndrome: A biochemical insight into Barrier-to-Autointegration Factor 1, alanine 12 threonine mutation
Publisher: Springer Science and Business Media LLC
Date: 12-2014
Transcriptional regulation in response to oxygen and nitrate of the operons encoding the [NiFe] hydrogenases 1 and 2 of Escherichia coli
Publisher: Microbiology Society
Date: 10-1999
DOI: 10.1099/00221287-145-10-2903
Abstract: Synthesis of the [NiFe] hydrogenases 1 and 2 of Escherichia coli is induced in response to anaerobiosis and is repressed when nitrate is present in the growth medium. The hydrogenase 1 and hydrogenase 2 enzymes are encoded by the polycistronic hyaABCDEF and hybOABCDEFG operons, respectively. Primer extension analysis was used to determine the initiation site of transcription of both operons. This permitted the construction of single-copy lacZ operon fusions, which were used to examine the transcriptional regulation of the two operons. Expression of both was induced by anaerobiosis and repressed by nitrate, which is in complete accord with earlier biochemical studies. Anaerobic induction of the hyb operon was only partially dependent on the FNR protein and, surprisingly, was enhanced by an arcA mutation. This latter result indicated that ArcA suppresses anaerobic hyb expression and that a further factor, which remains to be identified, is involved in controlling anaerobic induction of operon expression. Nitrate repression of hyb expression was mediated by the NarL/NarX and NarP/NarQ two-component regulatory systems. Remarkably, a narP mutant lacked anaerobic induction of hyb expression, even in the absence of added nitrate. Anaerobic induction of hya expression was dependent on the ArcA and AppY regulators, which confirms earlier observations by other authors. Nitrate repression of the hya operon was mediated by both NarL and NarP. Taken together, these data indicate that although the hya and hyb operons share common regulators, there are important differences in the control of expression of the in idual operons.
Human single-stranded DNA binding protein 1 (hSSB1/NABP2) is required for the stability and repair of stalled replication forks
Publisher: Oxford University Press (OUP)
Date: 20-04-2014
DOI: 10.1093/NAR/GKU276
Nicotine binds to the transthyretin-thyroxine complex and reduces its uptake by placental trophoblasts
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.MCE.2022.111642
Abstract: A supply of maternal thyroid hormone (thyroxine, T4) is essential for normal human fetal development. Human placental trophoblasts synthesize, secrete and take up the T4 binding protein transthyretin, providing a route for maternal T4 to enter the placenta. Transthyretin is also involved in T4 transport in other tissues such as the brain choroid plexus. Nicotine alters transthyretin synthesis and function in rat choroid plexus. If nicotine influences trophoblast turnover of transthyretin, then it may directly affect placental transfer of T4 to the developing fetus and contribute to the negative impacts of smoking on fetal growth, development and placental function. The effect of nicotine on trophoblast uptake of Alexa-labelled transthyretin was measured using live cell imaging. The effect of nicotine on protein expression was measured by western blotting. Interactions between transthyretin, T4 and nicotine were investigated using chemical cross-linking techniques and molecular dynamic simulations. Nicotine blocks uptake of transthyretin-T4 by human placental trophoblast cells. Nicotine reduces the expression of the trophoblast scavenger receptor class B type 1 (SR-B1) that plays a role in transthyretin-T4 uptake. Molecular dynamic modelling suggests that when T4 is bound to transthyretin, nicotine binding increases tetramer stability, reducing the ability of the transthyretin-T4 complex to enter trophoblast cells. Our data suggest that nicotine exposure during pregnancy reduces transplacental transport of transthyretin and T4 to the placenta and developing fetus. This may contribute to the negative effects of smoking on fetal growth, development and pregnancy viability.
WT1 interacts with MAD2 and regulates mitotic checkpoint function
Publisher: Springer Science and Business Media LLC
Date: 18-09-2014
DOI: 10.1038/NCOMMS5903
Human single-stranded DNA binding protein 1 (hSSB1, OBFC2B), a critical component of the DNA damage response
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.SEMCDB.2018.03.014
Abstract: Our genomic DNA is found predominantly in a double-stranded helical conformation. However, there are a number of cellular transactions and DNA damage events that result in the exposure of single stranded regions of DNA. DNA transactions require these regions of single stranded DNA, but they are only transient in nature as they are particularly susceptible to further damage through chemical and enzymatic degradation, metabolic activation, and formation of secondary structures. To protect these exposed regions of single stranded DNA, all living organisms have members of the Single Stranded DNA Binding (SSB) protein family, which are characterised by a conserved oligonucleotide/oligosaccharide-binding (OB) domain. In humans, three such proteins members have been identified namely the Replication Protein A (RPA) complex, hSSB1 and hSSB2. While RPA is extremely well characterised, the roles of hSSB1 and hSSB2 have only emerged recently. In this review, we discuss the critical roles that hSSB1 plays in the maintenance of genomic stability.
Physical and functional interaction of the archaeal single-stranded DNA-binding protein SSB with RNA polymerase
Publisher: Oxford University Press (OUP)
Date: 13-02-2004
DOI: 10.1093/NAR/GKH259
1st MICCAI workshop on deep learning in medical image analysis
Publisher: Informa UK Limited
Date: 05-04-2018
BRCA1 is an essential mediator of vinorelbine‐induced apoptosis in mesothelioma
Publisher: Wiley
Date: 19-03-2012
DOI: 10.1002/PATH.3979
Abstract: Therapeutic options for malignant pleural mesothelioma (MPM) are limited despite the increasing incidence globally. The vinca alkaloid vinorelbine exhibits clinical activity however, to date, treatment optimization has not been achieved using biomarkers. BRCA1 regulates sensitivity to microtubule poisons however, its role in regulating vinorelbine-induced apoptosis in mesothelioma is unknown. Here we demonstrate that BRCA1 plays an essential role in mediating vinorelbine-induced apoptosis, as evidenced by (1) the strong correlation between vinorelbine sensitivity and BRCA1 expression level (2) induction of resistance to vinorelbine by BRCA1 using siRNA oligonucleotides (3) dramatic down-regulation of BRCA1 following selection for vinorelbine resistance and (4) the re-activation of vinorelbine-induced apoptosis following re-expression of BRCA1 in resistant cells. To determine whether loss of BRCA1 expression in mesothelioma was potentially relevant in vivo, BRCA1 immunohistochemistry was subsequently performed on 144 primary mesothelioma specimens. Loss of BRCA1 protein expression was identified in 38.9% of s les. Together, these data suggest that BRCA1 plays a critical role in mediating apoptosis by vinorelbine in mesothelioma, warranting its clinical evaluation as a predictive biomarker.
PARP inhibition induces BAX/BAK‐independent synthetic lethality of BRCA1‐deficient non‐small cell lung cancer
Publisher: Wiley
Date: 27-06-2011
DOI: 10.1002/PATH.2925
Abstract: Evasion of apoptosis contributes to both tumourigenesis and drug resistance in non-small cell lung carcinoma (NSCLC). The pro-apoptotic BCL-2 family proteins BAX and BAK are critical regulators of mitochondrial apoptosis. New strategies for targeting NSCLC in a mitochondria-independent manner should bypass this common mechanism of apoptosis block. BRCA1 mutation frequency in lung cancer is low however, decreased BRCA1 mRNA and protein expression levels have been reported in a significant proportion of lung adenocarcinomas. BRCA1 mutation/deficiency confers a defect in homologous recombination DNA repair that has been exploited by synthetic lethality through inhibition of PARP (PARPi) in breast and ovarian cells however, it is not known whether this same synthetic lethal mechanism exists in NSCLC cells. Additionally, it is unknown whether the mitochondrial apoptotic pathway is required for BRCA1/PARPi-mediated synthetic lethality. Here we demonstrate that silencing of BRCA1 expression by RNA interference sensitizes NSCLC cells to PARP inhibition. Importantly, this sensitivity was not attenuated in cells harbouring mitochondrial apoptosis block induced by co-depletion of BAX and BAK. Furthermore, we demonstrate that BRCA1 inhibition cannot override platinum resistance, which is often mediated by loss of mitochondrial apoptosis signalling, but can still sensitize to PARP inhibition. Finally we demonstrate the existence of a BRCA1-deficient subgroup (11-19%) of NSCLC patients by analysing BRCA1 protein levels using immunohistochemistry in two independent primary NSCLC cohorts. Taken together, the existence of BRCA1-immunodeficient NSCLC suggests that this molecular subgroup could be effectively targeted by PARP inhibitors in the clinic and that PARP inhibitors could be used for the treatment of BRCA1-immunodeficient, platinum-resistant tumours.
Correction to: Vascular endothelial growth factor is an autocrine growth factor, signaling through neuropilin-1 in non-small cell lung cancer
Publisher: Springer Science and Business Media LLC
Date: 27-01-2020
DOI: 10.1186/S12943-020-1142-8
Abstract: Since the publication of this work [1] and in response to a recent query that was brought to our attention in relation to the Western Blot in Figure 1(C) for NP2, protein lysates prepared around the same time as those presented in the manuscript in question, were run by SDS-PAGE under similar experimental conditions and probed using the same primary antibodies to NP1 and NP2 that were used originally.
Expression of CDCA3 is a prognostic biomarker and potential therapeutic target in non-small cell lung cancer
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.JTHO.2017.04.018
Abstract: NSCLC is the leading cause for cancer-related deaths worldwide. New therapeutic targets are needed, as development of resistance to current treatment, such as platinum-based chemotherapy, is inevitable. The purpose of this study was to determine the functional relevance and therapeutic potential of cell ision cycle associated 3 protein (CDCA3) in NSCLC. The expression of CDCA3 in squamous and nonsquamous NSCLC was investigated by using bioinformatics, Western blot analysis of matched tumor and normal tissue, and immunohistochemistry of a tissue microarray. The function of CDCA3 in NSCLC was determined by using several in vitro assays with small interfering RNA depleting CDCA3 in a panel of three immortalized human bronchial epithelial cell (HBEC) lines and seven NSCLC cell lines. In this study, cell ision cycle associated 3 gene (CDCA3) transcripts were identified as highly increased in NSCLC versus in nonmalignant tissue, with high levels of CDCA3 being associated with poor patient prognosis. CDCA3 protein was also increased in NSCLC tissue and expression was limited to tumor cells. CDCA3 expression was similarly increased in a panel of NSCLC cell lines compared with in three HBEC lines. Although depletion of CDCA3 in the HBEC lines did not affect cellular proliferation, depletion of CDCA3 expression markedly reduced the proliferation of all NSCLC cell lines. CDCA3 depletion caused a defective G2/M-phase cell cycle progression, upregulation of p21 independent of p53, and induction of cellular senescence. Our findings highlight CDCA3 as a prognostic factor and potential novel therapeutic target in NSCLC through inhibition of tumor growth and promotion of tumor senescence.
Genome Stability Pathways in Head and Neck Cancers
Publisher: Hindawi Limited
Date: 2013
DOI: 10.1155/2013/464720
Abstract: Genomic instability underlies the transformation of host cells toward malignancy, promotes development of invasion and metastasis and shapes the response of established cancer to treatment. In this review, we discuss recent advances in our understanding of genomic stability in squamous cell carcinoma of the head and neck (HNSCC), with an emphasis on DNA repair pathways. HNSCC is characterized by distinct profiles in genome stability between similarly staged cancers that are reflected in risk, treatment response and outcomes. Defective DNA repair generates chromosomal derangement that can cause subsequent alterations in gene expression, and is a hallmark of progression toward carcinoma. Variable functionality of an increasing spectrum of repair gene polymorphisms is associated with increased cancer risk, while aetiological factors such as human papillomavirus, tobacco and alcohol induce significantly different behaviour in induced malignancy, underpinned by differences in genomic stability. Targeted inhibition of signalling receptors has proven to be a clinically-validated therapy, and protein expression of other DNA repair and signalling molecules associated with cancer behaviour could potentially provide a more refined clinical model for prognosis and treatment prediction. Development and expansion of current genomic stability models is furthering our understanding of HNSCC pathophysiology and uncovering new, promising treatment strategies.
Barrier-to-autointegration factor 1 (Banf1) regulates poly [ADP-ribose] polymerase 1 (PARP1) activity following oxidative DNA damage
Publisher: Springer Science and Business Media LLC
Date: 03-12-2019
DOI: 10.1038/S41467-019-13167-5
Abstract: The DNA repair capacity of human cells declines with age, in a process that is not clearly understood. Mutation of the nuclear envelope protein barrier-to-autointegration factor 1 (Banf1) has previously been shown to cause a human progeroid disorder, Néstor–Guillermo progeria syndrome (NGPS). The underlying links between Banf1, DNA repair and the ageing process are unknown. Here, we report that Banf1 controls the DNA damage response to oxidative stress via regulation of poly [ADP-ribose] polymerase 1 (PARP1). Specifically, oxidative lesions promote direct binding of Banf1 to PARP1, a critical NAD + -dependent DNA repair protein, leading to inhibition of PARP1 auto-ADP-ribosylation and defective repair of oxidative lesions, in cells with increased Banf1. Consistent with this, cells from patients with NGPS have defective PARP1 activity and impaired repair of oxidative lesions. These data support a model whereby Banf1 is crucial to reset oxidative-stress-induced PARP1 activity. Together, these data offer insight into Banf1-regulated, PARP1-directed repair of oxidative lesions.
68P Inflammatory meditated mechanisms of cisplatin resistance in non-small cell lung cancer
Publisher: Elsevier BV
Date: 04-2016
DNA damage contributes to transcriptional and immunological dysregulation of testicular cells during Chlamydia infection
Publisher: Wiley
Date: 20-02-2021
DOI: 10.1111/AJI.13400
Abstract: Chlamydia is the most commonly reported sexually transmitted bacterial infection, with 127 million notifications worldwide each year. Both males and females are susceptible to the pathological impacts on fertility that Chlamydia infections can induce. However, male chlamydial infections, particularly within the upper reproductive tract, including the testis, are not well characterized. In this study, using mouse testicular cell lines, we examined the impact of infection on testicular cell lineage transcriptomes and potential mechanisms for this impact. The somatic cell lineages exhibited significantly fragmented genomes during infection. Likely resulting from this, each of the Leydig, Sertoli and germ cell lineages experienced extensive transcriptional dysregulation, leading to significant changes in cellular biological pathways, including interferon and germ‐Sertoli cell signalling. The cell lineages, as well as isolated spermatozoa from infected mice, also contained globally hypomethylated DNA. Cumulatively, the DNA damage and epigenetic‐mediated transcriptional dysregulation observed within testicular cells during chlamydial infection could result in the production of spermatozoa with abnormal epigenomes, resulting in previously observed subfertility in infected animals and congenital defects in their offspring.
4 Inhibition of PARP activity by PJ34 sensitises NSCLC cells to cisplatin
Publisher: Elsevier BV
Date: 2014
Crystallization and preliminary X-ray diffraction studies of Hje, a Holliday junction resolving enzyme from Sulfolobus solfataricus
Publisher: International Union of Crystallography (IUCr)
Date: 20-12-2002
DOI: 10.1107/S0907444902019546
Abstract: HolliDay junction endonuclease (Hje) from Sulfolobus solfataricus is a resolving enzyme involved in cleaving specific sites on either side of recombinant four-way HolliDay junctions. The HJE gene from S. solfataricus was cloned from genomic DNA into the pET19b Escherichia coli expression vector and recombinant protein was expressed to high levels. Hje was purified using heat treatment, cation exchange and gel filtration. Hanging-drop crystallization trials yielded primitive hexagonal crystals which diffract to 2.4 A on a laboratory source. Systematic absences (only 00l = 6n present) and poor scaling in P622 indicate that the space group is P6(1) or its enantiomer. Failed attempts at molecular replacement using models of a related archaeal resolving enzyme, Hjc, raise the possibility of a difference in quaternary structure between Hjc and Hje, which may be responsible for differences in their activities.
Evidence of a putative glycosaminoglycan binding site on the glycosylated SARS-CoV-2 spike protein N-terminal domain
Publisher: Elsevier BV
Date: 2021
Human single-stranded DNA binding proteins are essential for maintaining genomic stability
Publisher: Springer Science and Business Media LLC
Date: 04-2013
Abstract: The double-stranded conformation of cellular DNA is a central aspect of DNA stabilisation and protection. The helix preserves the genetic code against chemical and enzymatic degradation, metabolic activation, and formation of secondary structures. However, there are various instances where single-stranded DNA is exposed, such as during replication or transcription, in the synthesis of chromosome ends, and following DNA damage. In these instances, single-stranded DNA binding proteins are essential for the sequestration and processing of single-stranded DNA. In order to bind single-stranded DNA, these proteins utilise a characteristic and evolutionary conserved single-stranded DNA-binding domain, the oligonucleotide/oligosaccharide-binding (OB)-fold. In the current review we discuss a subset of these proteins involved in the direct maintenance of genomic stability, an important cellular process in the conservation of cellular viability and prevention of malignant transformation. We discuss the central roles of single-stranded DNA binding proteins from the OB-fold domain family in DNA replication, the restart of stalled replication forks, DNA damage repair, cell cycle-checkpoint activation, and telomere maintenance.
2 MicroRNA profiling and cisplatin–DNA interactions in an isogenic model of cisplatin resistant NSCLC cell lines
Publisher: Elsevier BV
Date: 2013
P3.01-042 Lung Cancer Cells Can Stimulate Functional and Genotypic Modifications in Normal Bronchial Epithelial Cells
Publisher: Elsevier BV
Date: 2017
Elevating CDCA3 levels in non-small cell lung cancer enhances sensitivity to platinum-based chemotherapy
Publisher: Springer Science and Business Media LLC
Date: 28-05-2021
DOI: 10.1038/S42003-021-02136-8
Abstract: Platinum-based chemotherapy remains the cornerstone of treatment for most non-small cell lung cancer (NSCLC) cases either as maintenance therapy or in combination with immunotherapy. However, resistance remains a primary issue. Our findings point to the possibility of exploiting levels of cell ision cycle associated protein-3 (CDCA3) to improve response of NSCLC tumours to therapy. We demonstrate that in patients and in vitro analyses, CDCA3 levels correlate with measures of genome instability and platinum sensitivity, whereby CDCA3 high tumours are sensitive to cisplatin and carboplatin. In NSCLC, CDCA3 protein levels are regulated by the ubiquitin ligase APC/C and cofactor Cdh1. Here, we identified that the degradation of CDCA3 is modulated by activity of casein kinase 2 (CK2) which promotes an interaction between CDCA3 and Cdh1. Supporting this, pharmacological inhibition of CK2 with CX-4945 disrupts CDCA3 degradation, elevating CDCA3 levels and increasing sensitivity to platinum agents. We propose that combining CK2 inhibitors with platinum-based chemotherapy could enhance platinum efficacy in CDCA3 low NSCLC tumours and benefit patients.
74P Elucidating drug resistance mechanisms using 2D and 3D culture systems
Publisher: Elsevier BV
Date: 04-2016
Epigenetic Mechanisms in DNA Double Strand Break Repair: A Clinical Review
Publisher: Frontiers Media SA
Date: 07-07-2021
DOI: 10.3389/FMOLB.2021.685440
Abstract: Upon the induction of DNA damage, the chromatin structure unwinds to allow access to enzymes to catalyse the repair. The regulation of the winding and unwinding of chromatin occurs via epigenetic modifications, which can alter gene expression without changing the DNA sequence. Epigenetic mechanisms such as histone acetylation and DNA methylation are known to be reversible and have been indicated to play different roles in the repair of DNA. More importantly, the inhibition of such mechanisms has been reported to play a role in the repair of double strand breaks, the most detrimental type of DNA damage. This occurs by manipulating the chromatin structure and the expression of essential proteins that are critical for homologous recombination and non-homologous end joining repair pathways. Inhibitors of histone deacetylases and DNA methyltransferases have demonstrated efficacy in the clinic and represent a promising approach for cancer therapy. The aims of this review are to summarise the role of histone deacetylase and DNA methyltransferase inhibitors involved in DNA double strand break repair and explore their current and future independent use in combination with other DNA repair inhibitors or pre-existing therapies in the clinic.
Epigenetic Therapy in Lung Cancer and Mesothelioma
Publisher: Elsevier
Date: 2015
Defining COMMD4 as an anti-cancer therapeutic target and prognostic factor in non-small cell lung cancer
Publisher: Springer Science and Business Media LLC
Date: 22-05-2020
DOI: 10.1038/S41416-020-0899-2
Abstract: Non-small cell lung cancers (NSCLC) account for 85–90% of all lung cancers. As drug resistance critically impairs chemotherapy effectiveness, there is great need to identify new therapeutic targets. The aims of this study were to investigate the prognostic and therapeutic potential of the copper-metabolism-domain-protein, COMMD4, in NSCLC. The expression of COMMD4 in NSCLC was investigated using bioinformatic analysis, immunoblotting of immortalised human bronchial epithelial (HBEC) and NSCLC cell lines, qRT-PCR and immunohistochemistry of tissue microarrays. COMMD4 function was additionally investigated in HBEC and NSCLC cells depleted of COMMD4, using small interfering RNA sequences. Bioinformatic analysis and in vitro analysis of COMMD4 transcripts showed that COMMD4 levels were upregulated in NSCLC and elevated COMMD4 was associated with poor prognosis in adenocarcinoma (ADC). Immunoblotting demonstrated that COMMD4 expression was upregulated in NSCLC cells and siRNA-depletion of COMMD4, decreased cell proliferation and reduced cell viability. Cell death was further enhanced after exposure to DNA damaging agents. COMMD4 depletion caused NSCLC cells to undergo mitotic catastrophe and apoptosis. Our data indicate that COMMD4 may function as a prognostic factor in ADC NSCLC. Additionally, COMMD4 is a potential therapeutic target for NSCLC, as its depletion induces cancer cell death.
HSSB1 (NABP2/OBFC2B) is required for the repair of 8-oxo-guanine by the hOGG1-mediated base excision repair pathway
Publisher: Oxford University Press (OUP)
Date: 10-08-2015
DOI: 10.1093/NAR/GKV790
Novel insight into the composition of human single-stranded DNA-binding protein 1 (hSSB1)-containing protein complexes
Publisher: Springer Science and Business Media LLC
Date: 12-2016
Nucleophosmin: From structure and function to disease development
Publisher: Springer Science and Business Media LLC
Date: 24-08-2016
High-Plex and High-Throughput Digital Spatial Profiling of Non-Small-Cell Lung Cancer (NSCLC)
Publisher: MDPI AG
Date: 27-11-2020
Abstract: Profiling the tumour microenvironment (TME) has been informative in understanding the underlying tumour–immune interactions. Multiplex immunohistochemistry (mIHC) coupled with molecular barcoding technologies have revealed greater insights into the TME. In this study, we utilised the Nanostring GeoMX Digital Spatial Profiler (DSP) platform to profile a non-small-cell lung cancer (NSCLC) tissue microarray for protein markers across immune cell profiling, immuno-oncology (IO) drug targets, immune activation status, immune cell typing, and pan-tumour protein modules. Regions of interest (ROIs) were selected that described tumour, TME, and normal adjacent tissue (NAT) compartments. Our data revealed that paired analysis (n = 18) of matched patient compartments indicate that the TME was significantly enriched in CD27, CD3, CD4, CD44, CD45, CD45RO, CD68, CD163, and VISTA relative to the tumour. Unmatched analysis indicated that the NAT (n = 19) was significantly enriched in CD34, fibronectin, IDO1, LAG3, ARG1, and PTEN when compared to the TME (n = 32). Univariate Cox proportional hazards indicated that the presence of cells expressing CD3 (hazard ratio (HR): 0.5, p = 0.018), CD34 (HR: 0.53, p = 0.004), and ICOS (HR: 0.6, p = 0.047) in tumour compartments were significantly associated with improved overall survival (OS). We implemented both high-plex and high-throughput methodologies to the discovery of protein biomarkers and molecular phenotypes within biopsy s les, and demonstrate the power of such tools for a new generation of pathology research.
Multiple human single-stranded DNA binding proteins function in genome maintenance: Structural, biochemical and functional analysis Human single-stranded DNA binding proteins D. J. Richard et al.
Publisher: Informa UK Limited
Date: 06-2009
DOI: 10.1080/10409230902849180
Abstract: DNA exists predominantly in a duplex form that is preserved via specific base pairing. This base pairing affords a considerable degree of protection against chemical or physical damage and preserves coding potential. However, there are many situations, e.g. during DNA damage and programmed cellular processes such as DNA replication and transcription, in which the DNA duplex is separated into two single-stranded DNA (ssDNA) strands. This ssDNA is vulnerable to attack by nucleases, binding by inappropriate proteins and chemical attack. It is very important to control the generation of ssDNA and protect it when it forms, and for this reason all cellular organisms and many viruses encode a ssDNA binding protein (SSB). All known SSBs use an oligosaccharide/oligonucleotide binding (OB)-fold domain for DNA binding. SSBs have multiple roles in binding and sequestering ssDNA, detecting DNA damage, stimulating strand-exchange proteins and helicases, and mediation of protein-protein interactions. Recently two additional human SSBs have been identified that are more closely related to bacterial and archaeal SSBs. Prior to this it was believed that replication protein A, RPA, was the only human equivalent of bacterial SSB. RPA is thought to be required for most aspects of DNA metabolism including DNA replication, recombination and repair. This review will discuss in further detail the biological pathways in which human SSBs function.
HSSB1 interacts directly with the MRN complex stimulating its recruitment to DNA double-strand breaks and its endo-nuclease activity
Publisher: Oxford University Press (OUP)
Date: 10-01-2011
DOI: 10.1093/NAR/GKQ1340
1 Targeting NF-κB regulated pathways to overcome cisplatin resistance in non-small cell lung cancer
Publisher: Elsevier BV
Date: 2014
Sex Hormone Binding Globulin Modifies Testosterone Action and Metabolism in Prostate Cancer Cells
Publisher: Hindawi Limited
Date: 2016
DOI: 10.1155/2016/6437585
Abstract: Sex Hormone Binding Globulin (SHBG) is the major serum carrier of sex hormones. However, growing evidence suggests that SHBG is internalised and plays a role in regulating intracellular hormone action. This study was to determine whether SHBG plays a role in testosterone uptake, metabolism, and action in the androgen sensitive LNCaP prostate cancer cell line. Internalisation of SHBG and testosterone, the effects of SHBG on testosterone uptake, metabolism, regulation of androgen responsive genes, and cell growth were assessed. LNCaP cells internalised SHBG by a testosterone independent process. Testosterone was rapidly taken up and effluxed as testosterone-glucuronide however this effect was reduced by the presence of SHBG. Addition of SHBG, rather than reducing testosterone bioavailability, further increased testosterone-induced expression of prostate specific antigen and enhanced testosterone-induced reduction of androgen receptor mRNA expression. Following 38 hours of testosterone treatment cell morphology changed and growth declined however, cotreatment with SHBG abrogated these inhibitory effects. These findings clearly demonstrate that internalised SHBG plays an important regulatory and intracellular role in modifying testosterone action and this has important implications for the role of SHBG in health and disease.
Transcriptomic profiling of cardiac tissues from SARS‐CoV‐2 patients identifies DNA damage
Publisher: Wiley
Date: 27-09-2023
DOI: 10.1111/IMM.13577
Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is known to present with pulmonary and extra‐pulmonary organ complications. In comparison with the 2009 pandemic (pH1N1), SARS‐CoV‐2 infection is likely to lead to more severe disease, with multi‐organ effects, including cardiovascular disease. SARS‐CoV‐2 has been associated with acute and long‐term cardiovascular disease, but the molecular changes that govern this remain unknown. In this study, we investigated the host transcriptome landscape of cardiac tissues collected at rapid autopsy from seven SARS‐CoV‐2, two pH1N1, and six control patients using targeted spatial transcriptomics approaches. Although SARS‐CoV‐2 was not detected in cardiac tissue, host transcriptomics showed upregulation of genes associated with DNA damage and repair, heat shock, and M1‐like macrophage infiltration in the cardiac tissues of COVID‐19 patients. The DNA damage present in the SARS‐CoV‐2 patient s les, were further confirmed by γ‐H2Ax immunohistochemistry. In comparison, pH1N1 showed upregulation of interferon‐stimulated genes, in particular interferon and complement pathways, when compared with COVID‐19 patients. These data demonstrate the emergence of distinct transcriptomic profiles in cardiac tissues of SARS‐CoV‐2 and pH1N1 influenza infection supporting the need for a greater understanding of the effects on extra‐pulmonary organs, including the cardiovascular system of COVID‐19 patients, to delineate the immunopathobiology of SARS‐CoV‐2 infection, and long term impact on health.
Deciphering the growth, organic acid exudations, and ionic homeostasis of Amaranthus viridis L. and Portulaca oleracea L. under lead chloride stress
Publisher: Springer Science and Business Media LLC
Date: 16-11-2017
DOI: 10.1007/S11356-017-0735-2
Abstract: Lead (Pb) stress adversely affects in planta nutrient homeostasis and metabolism when present at elevated concentration in the surrounding media. The present study was aimed at investigation of organic acid exudations, elemental contents, growth, and lipid peroxidation in two wild plants (Amaranthus viridis L. and Portulaca oleracea L.), exhibiting differential root to shoot Pb translocation, under Pb stress. Plants were placed in soil spiked with lead chloride (PbCl
Par4 is a coactivator for a splice isoform–specific transcriptional activation domain in WT1
Publisher: Cold Spring Harbor Laboratory
Date: 02-2001
DOI: 10.1101/GAD.185901
Abstract: The Wilms' tumor suppressor protein WT1 is a transcriptional regulator involved in differentiation and the regulation of cell growth. WT1 is subject to alternative splicing, one isoform including a 17–amino acid region that is specific to mammals. The function of this 17–amino acid insertion is not clear, however. Here, we describe a transcriptional activation domain in WT1 that is specific to the WT1 splice isoform that contains the 17–amino acid insertion. We show that the function of this domain in transcriptional activation is dependent on a specific interaction with the prostate apoptosis response factor par4. A mutation in WT1 found in Wilms' tumor disturbs the interaction with par4 and disrupts the function of the activation domain. Analysis of WT1 derivatives in cells treated to induce par4 expression showed a strong correlation between the transcription function of the WT1 17–amino acid insertion and the ability of WT1 to regulate cell survival and proliferation. Our results provide a molecular mechanism by which alternative splicing of WT1 can regulate cell growth in development and disease.
The identification of circulating tumour DNA using MassARRAY technology in non-small-cell lung cancer (NSCLC)
Publisher: Elsevier BV
Date: 10-2021
A distinct ssDNA /RNA binding interface in the Nsp9 protein from SARS‐CoV ‐2
Publisher: Wiley
Date: 13-08-2021
DOI: 10.1002/PROT.26205
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a novel, highly infectious RNA virus that belongs to the coronavirus family. Replication of the viral genome is a fundamental step in the virus life cycle and SARS‐CoV‐2 non‐structural protein 9 (Nsp9) is shown to be essential for virus replication through its ability to bind RNA in the closely related SARS‐CoV‐1 strain. Two recent studies revealing the three‐dimensional structure of Nsp9 from SARS‐CoV‐2 have demonstrated a high degree of similarity between Nsp9 proteins within the coronavirus family. However, the binding affinity to RNA is very low which, until now, has prevented the determination of the structural details of this interaction. In this study, we have utilized nuclear magnetic resonance spectroscopy (NMR) in combination with surface biolayer interferometry (BLI) to reveal a distinct binding interface for both ssDNA and RNA that is different to the one proposed in the recently solved SARS‐CoV‐2 replication and transcription complex (RTC) structure. Based on these data, we have proposed a structural model of a Nsp9‐RNA complex, shedding light on the molecular details of these important interactions.
Human single-stranded DNA protein 1 (hSSB1): a new prognostic tool and target for non-small cell lung cancer treatment
Publisher: Elsevier BV
Date: 2019
SASH1 is a prognostic indicator and potential therapeutic target in non-small cell lung cancer
Publisher: Springer Science and Business Media LLC
Date: 29-10-2020
DOI: 10.1038/S41598-020-75625-1
Abstract: SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor protein that has roles in key cellular processes including apoptosis and cellular proliferation. As these cellular processes are frequently disrupted in human tumours and little is known about the role of SASH1 in the pathogenesis of the disease, we analysed the prognostic value of SASH1 in non-small cell lung cancers using publicly available datasets. Here, we show that low SASH1 mRNA expression is associated with poor survival in adenocarcinoma. Supporting this, modulation of SASH1 levels in a panel of lung cancer cell lines mediated changes in cellular proliferation and sensitivity to cisplatin. The treatment of lung cancer cells with chloropyramine, a compound that increases SASH1 protein concentrations, reduced cellular proliferation and increased sensitivity to cisplatin in a SASH1-dependent manner. In summary, compounds that increase SASH1 protein levels could represent a novel approach to treat NSCLC and warrant further study.
12 VEGF autocrine survival signalling is mediated via neuropilin 1 receptor in NSCLC cells
Publisher: Elsevier BV
Date: 2014
The role of DNA repair pathways in cisplatin resistant lung cancer
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.CTRV.2014.10.003
Abstract: Platinum chemotherapeutic agents such as cisplatin are currently used in the treatment of various malignancies such as lung cancer. However, their efficacy is significantly hindered by the development of resistance during treatment. While a number of factors have been reported that contribute to the onset of this resistance phenotype, alterations in the DNA repair capacity of damaged cells is now recognised as an important factor in mediating this phenomenon. The mode of action of cisplatin has been linked to its ability to crosslink purine bases on the DNA, thereby interfering with DNA repair mechanisms and inducing DNA damage. Following DNA damage, cells respond by activating a DNA-damage response that either leads to repair of the lesion by the cell thereby promoting resistance to the drug, or cell death via activation of the apoptotic response. Therefore, DNA repair is a vital target to improving cancer therapy and reduce the resistance of tumour cells to DNA damaging agents currently used in the treatment of cancer patients. To date, despite the numerous findings that differential expression of components of the various DNA repair pathways correlate with response to cisplatin, translation of such findings in the clinical setting are still warranted. The identification of alterations in specific proteins and pathways that contribute to these unique DNA repair pathways in cisplatin resistant cancer cells may potentially lead to a renewed interest in the development of rational novel therapies for cisplatin resistant cancers, in particular, lung cancer.
COMMD4 functions with the histone H2A-H2B dimer for the timely repair of DNA double-strand breaks
Publisher: Springer Science and Business Media LLC
Date: 19-04-2021
DOI: 10.1038/S42003-021-01998-2
Abstract: Genomic stability is critical for normal cellular function and its deregulation is a universal hallmark of cancer. Here we outline a previously undescribed role of COMMD4 in maintaining genomic stability, by regulation of chromatin remodelling at sites of DNA double-strand breaks. At break-sites, COMMD4 binds to and protects histone H2B from monoubiquitination by RNF20/RNF40. DNA damage-induced phosphorylation of the H2A-H2B heterodimer disrupts the dimer allowing COMMD4 to preferentially bind H2A. Displacement of COMMD4 from H2B allows RNF20/40 to monoubiquitinate H2B and for remodelling of the break-site. Consistent with this critical function, COMMD4-deficient cells show excessive elongation of remodelled chromatin and failure of both non-homologous-end-joining and homologous recombination. We present peptide-mapping and mutagenesis data for the potential molecular mechanisms governing COMMD4-mediated chromatin regulation at DNA double-strand breaks.
Genome Instability and Pressure on Non-Homologous end Joining drives Chemotherapy Resistance via a DNA Repair Crisis Switch in Triple Negative Breast Cancer.
Publisher: Research Square Platform LLC
Date: 12-11-2020
DOI: 10.21203/RS.3.RS-103661/V1
Abstract: Background: Chemotherapy intensifies pressure on the DNA repair pathways that can lead to deregulation. There is an urgent clinical need to be able to track the emergence of chemotherapy resistance and tailor patient staging appropriately. This is especially evident in the triple negative breast cancer (TNBC) subtype, of which standard of care is chemotherapy with tumours displaying high levels of inherent genome instability. TNBC has an overall poor prognosis for survival. There have been numerous studies into single agent chemoresistance but to date no study has elucidated in detail the roles of the key DNA repair components in resistance associated with the frontline clinical combination of anthracyclines and taxanes together. Methods: In this study, we hypothesized that the emergence of chemotherapy resistance is driven by changes in functional signaling in the DNA repair pathways. We identified the importance of the DNA repair pathways in chemoresistant clinical s les and characterized the emergence of chemoresistance in TNBC cell lines. We utilized classical DNA repair assays and specific targeting of key DNA repair proteins to elucidate a new mechanism for adaptation to the combination of doxorubicin and docetaxel. Results: We identified that consistent pressure on the non-homologous end joining pathway in the presence of genome instability causes failure of the key kinase DNA-PK, loss of p53 and compensation by p73. In-turn a switch to reliance on the homologous recombination pathway and RAD51 recombinase occurs to repair residual double strand DNA breaks. Conclusions: We demonstrate that RAD51 is an actionable target for resensitization to chemotherapy in resistant cells with a matched gene expression profile of resistance highlighted by homologous recombination.
The structural details of the interaction of single-stranded DNA binding protein hSSB2 (NABP1/OBFC2A) with UV-damaged DNA.
Publisher: Wiley
Date: 30-08-2020
DOI: 10.1002/PROT.25806
Abstract: Single-stranded DNA-binding proteins (SSBs) are required for all known DNA metabolic events such as DNA replication, recombination and repair. While a wealth of structural and functional data is available on the essential human SSB, hSSB1 (NABP2/OBFC2B), the close homolog hSSB2 (NABP1/OBFC2A) remains relatively uncharacterized. Both SSBs possess a well-structured OB (oligonucleotide/oligosaccharide-binding) domain that is able to recognize single-stranded DNA (ssDNA) followed by a flexible carboxyl-tail implicated in the interaction with other proteins. Despite the high sequence similarity of the OB domain, several recent studies have revealed distinct functional differences between hSSB1 and hSSB2. In this study, we show that hSSB2 is able to recognize cyclobutane pyrimidine dimers (CPD) that form in cellular DNA as a consequence of UV damage. Using a combination of biolayer interferometry and NMR, we determine the molecular details of the binding of the OB domain of hSSB2 to CPD-containing ssDNA, confirming the role of four key aromatic residues in hSSB2 (W59, Y78, W82, and Y89) that are also conserved in hSSB1. Our structural data thus demonstrate that ssDNA recognition by the OB fold of hSSB2 is highly similar to hSSB1, indicating that one SSB may be able to replace the other in any initial ssDNA binding event. However, any subsequent recruitment of other repair proteins most likely depends on the ergent carboxyl-tail and as such is likely to be different between hSSB1 and hSSB2.
COMMD4 Functions with the Histone H2A-H2B Dimer for the Timely Repair of DNA Double Strand Breaks
Publisher: Elsevier BV
Date: 2020
DOI: 10.2139/SSRN.3516893
Poster Presentations
Publisher: Wiley
Date: 06-2008
Correction
Publisher: Springer Science and Business Media LLC
Date: 26-01-2021
DOI: 10.1038/S41416-020-01242-4
Abstract: A Correction to this paper has been published: 0.1038/s41416-020-01242-4.
Single-Stranded DNA Binding Proteins Involved in Genome Maintenance
Publisher: Springer Netherlands
Date: 2009
Krüppel-associated box (KRAB)-associated co-repressor (KAP-1) Ser-473 phosphorylation regulates heterochromatin protein 1β (HP1-β) mobilization and DNA repair in heterochromatin
Publisher: Elsevier BV
Date: 08-2012
hSSB1 associates with and promotes stability of the BLM helicase
Publisher: Springer Science and Business Media LLC
Date: 15-05-2017
Tumor Hypoxia Drives Genomic Instability
Publisher: Frontiers Media SA
Date: 16-03-2021
DOI: 10.3389/FCELL.2021.626229
Abstract: Cancer is a leading cause of death worldwide. As a common characteristic of cancer, hypoxia is associated with poor prognosis due to enhanced tumor malignancy and therapeutic resistance. The enhanced tumor aggressiveness stems at least partially from hypoxia-induced genomic instability. Therefore, a clear understanding of how tumor hypoxia induces genomic instability is crucial for the improvement of cancer therapeutics. This review summarizes recent developments highlighting the association of tumor hypoxia with genomic instability and the mechanisms by which tumor hypoxia drives genomic instability, followed by how hypoxic tumors can be specifically targeted to maximize efficacy.
The Emerging Role of Gas Plasma in Oncotherapy
Publisher: Elsevier BV
Date: 11-2018
DOI: 10.1016/J.TIBTECH.2018.06.010
Abstract: Atmospheric pressure gas plasmas are emerging as a promising treatment in cancer that can supplement the existing set of treatment modalities and, when combined with other therapies, enhance their selectivity and efficacy against resistant cancers. With further optimisation in production and administration of plasma treatment, plasma-enabled therapy has a strong potential to mature as a tool for selectively curing highly resistant solid tumours. Although intense preclinical studies have been conducted to exploit the unique traits of plasma as an oncotherapy, few clinical studies are underway. This review identifies types of cancers and patient groups that most likely benefit from plasma oncotherapy, to introduce clinical practitioners to plasma therapy and accelerate the speed of translating plasma for cancer control in clinics.
Spatiotemporal investigations of DNA damage repair using microbeams
Publisher: Oxford University Press (OUP)
Date: 12-12-2010
DOI: 10.1093/RPD/NCQ485
Abstract: Cellular response to radiation damage is made by a complex network of pathways and feedback loops whose spatiotemporal organisation is still unclear despite its decisive role in determining the fate of the damaged cell. Revealing the dynamic sequence of the repair proteins is therefore critical in understanding how the DNA repair mechanisms work. There are also still open questions regarding the possible movement of damaged chromatin domains and its role as trigger for lesion recognition and signalling in the DNA repair context. The single-cell approach and the high spatial resolution offered by microbeams provide the perfect tool to study and quantify the dynamic processes associated with the induction and repair of DNA damage. We have followed the development of radiation-induced foci for three DNA damage markers (i.e. γ-H2AX, 53BP1 and hSSB1) using normal fibroblasts (AG01522), human breast adenocarcinoma cells (MCF7) and human fibrosarcoma cells (HT1080) stably transfected with yellow fluorescent protein fusion proteins following irradiation with the QUB X-ray microbeam (carbon X-rays <2 µm spot). The size and intensity of the foci has been analysed as a function of dose and time post-irradiation to investigate the dynamics of the above-mentioned DNA repair processes and monitor the remodelling of chromatin structure that the cell undergoes to deal with DNA damage.
Generation and Characterisation of Cisplatin-Resistant Non-Small Cell Lung Cancer Cell Lines Displaying a Stem-Like Signature
Publisher: Public Library of Science (PLoS)
Date: 17-01-2013
Elucidating distinct oxidative stress management, nutrient acquisition and yield responses of Pisum sativum L. fertigated with diluted and treated wastewater
Publisher: Elsevier BV
Date: 03-2021
Enhancing sensitivity to platinum-based therapy by suppressing the novel prognostic factor CDCA3 in non- small cell lung cancer
Publisher: Elsevier BV
Date: 2019
Correction: Generation and Characterisation of Cisplatin-Resistant Non-Small Cell Lung Cancer Cell Lines Displaying a Stem-Like Signature
Publisher: Public Library of Science (PLoS)
Date: 21-05-2020
Promotion of a cancer-like phenotype, through chronic exposure to inflammatory cytokines and hypoxia in a bronchial epithelial cell line model
Publisher: Springer Science and Business Media LLC
Date: 13-01-2016
DOI: 10.1038/SREP18907
Abstract: Globally, lung cancer accounts for approximately 20% of all cancer related deaths. Five-year survival is poor and rates have remained unchanged for the past four decades. There is an urgent need to identify markers of lung carcinogenesis and new targets for therapy. Given the recent successes of immune modulators in cancer therapy and the improved understanding of immune evasion by tumours, we sought to determine the carcinogenic impact of chronic TNF-α and IL-1β exposure in a normal bronchial epithelial cell line model. Following three months of culture in a chronic inflammatory environment under conditions of normoxia and hypoxia (0.5% oxygen), normal cells developed a number of key genotypic and phenotypic alterations. Important cellular features such as the proliferative, adhesive and invasive capacity of the normal cells were significantly lified. In addition, gene expression profiles were altered in pathways associated with apoptosis, angiogenesis and invasion. The data generated in this study provides support that TNF-α, IL-1β and hypoxia promotes a neoplastic phenotype in normal bronchial epithelial cells. In turn these mediators may be of benefit for biomarker and/or immune-therapy target studies. This project provides an important inflammatory in vitro model for further immuno-oncology studies in the lung cancer setting.
Erratum: Chemo-Radiative Stress of Plasma as a Modulator of Charge-Dependent Nanodiamond Cytotoxicity (ACS Appl. Bio Mater. (2020 )3 : 10 (7202−7210) DOI: 10.1021/acsabm.0c01000)
Publisher: American Chemical Society (ACS)
Date: 24-02-2021
Modelling reoxygenation effects in non-small cell lung cancer cell lines and showing epithelial-mesenchymal transition
Publisher: Springer Science and Business Media LLC
Date: 06-08-2022
DOI: 10.1007/S00432-022-04242-4
Abstract: Circulating tumour cells (CTCs) are a rare cell subpopulation regulated by the tumour microenvironment. In hypoxic conditions, CTCs are able to invade the lymphatic and circulatory systems leading to metastasis at distant sites. To mimic in vivo oxygen variations and effects on CTCs, we have cultured five non-small cell lung cancer (NSCLC) cell lines under normoxic and hypoxic conditions, followed by a pulse of reoxygenation for 4 h. Proliferation, spheroid-formation and colony formation ability under varying O 2 levels were investigated. Proliferation rate was not altered when cells were cultured in 2D models under hypoxic conditions. However, we observed that hypoxia enhanced in vitro formation of tumour-spheres and accelerated clonogenicity of NSCLC cell lines. In addition, cells exposed to hypoxia and reoxygenation conditions showed altered expression of epithelial-mesenchymal transition (EMT) related genes in NSCLC cell lines both at mRNA (AKT1, CAMK2NH1, DESI1, VIM, MAP1B, EGFR, ZEB1, HIF1α) and protein levels (Vimentin, Pan-cytokeratin). Our data suggest that when investigating CTCs as a prognostic biomarker in NSCLC, it is also essential to take into consideration EMT status to obtain a comprehensive overview of CTCs in circulation.
Transcriptomic profiling of cardiac tissues from SARS-CoV-2 patients identifies DNA damage
Publisher: Cold Spring Harbor Laboratory
Date: 31-03-2022
DOI: 10.1101/2022.03.24.22272732
Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to present with pulmonary and extra-pulmonary organ complications. In comparison with the 2009 pandemic (pH1N1), SARS-CoV-2 infection is likely to lead to more severe disease, with multi-organ effects, including cardiovascular disease. SARS-CoV-2 has been associated with acute and long-term cardiovascular disease, but the molecular changes govern this remain unknown. In this study, we investigated the landscape of cardiac tissues collected at rapid autopsy from SARS-CoV-2, pH1N1, and control patients using targeted spatial transcriptomics approaches. Although SARS-CoV-2 was not detected in cardiac tissue, host transcriptomics showed upregulation of genes associated with DNA damage and repair, heat shock, and M1-like macrophage infiltration in the cardiac tissues of COVID-19 patients. The DNA damage present in the SARS-CoV-2 patient s les, were further confirmed by γ−H2Ax immunohistochemistry. In comparison, pH1N1 showed upregulation of Interferon-stimulated genes (ISGs), in particular interferon and complement pathways, when compared with COVID-19 patients. These data demonstrate the emergence of distinct transcriptomic profiles in cardiac tissues of SARS-CoV-2 and pH1N1 influenza infection supporting the need for a greater understanding of the effects on extra-pulmonary organs, including the cardiovascular system of COVID-19 patients, to delineate the immunopathobiology of SARS-CoV-2 infection, and long term impact on health.
Integration of molecular modelling and in vitro studies to inhibit LexA proteolysis
Publisher: Frontiers Media SA
Date: 03-03-2023
DOI: 10.3389/FCIMB.2023.1051602
Abstract: As antibiotic resistance has become more prevalent, the social and economic impacts are increasingly pressing. Indeed, bacteria have developed the SOS response which facilitates the evolution of resistance under genotoxic stress. The transcriptional repressor, LexA, plays a key role in this response. Mutation of LexA to a non-cleavable form that prevents the induction of the SOS response sensitizes bacteria to antibiotics. Achieving the same inhibition of proteolysis with small molecules also increases antibiotic susceptibility and reduces drug resistance acquisition. The availability of multiple LexA crystal structures, and the unique Ser-119 and Lys-156 catalytic dyad in the protein enables the rational design of inhibitors. We pursued a binary approach to inhibit proteolysis we first investigated β-turn mimetics, and in the second approach we tested covalent warheads targeting the Ser-119 residue. We found that the cleavage site region (CSR) of the LexA protein is a classical Type II β-turn, and that published 1,2,3-triazole compounds mimic the β-turn. Generic covalent molecule libraries and a β-turn mimetic library were docked to the LexA C-terminal domain using molecular modelling methods in FlexX and CovDock respectively. The 133 highest-scoring molecules were screened for their ability to inhibit LexA cleavage under alkaline conditions. The top molecules were then tested using a RecA-mediated cleavage assay. The β-turn library screen did not produce any hit compounds that inhibited RecA-mediated cleavage. The covalent screen discovered an electrophilic serine warhead that can inhibit LexA proteolysis, reacting with Ser-119 via a nitrile moiety. This research presents a starting point for hit-to-lead optimisation, which could lead to inhibition of the SOS response and prevent the acquisition of antibiotic resistance.
The molecular details of a novel phosphorylation-dependent interaction between MRN and the SOSS complex
Publisher: Wiley
Date: 26-09-2023
DOI: 10.1002/PRO.4782
A Structural Perspective on the Regulation of Human Single-Stranded DNA Binding Protein 1 (hSSB1, OBFC2B) Function in DNA Repair
Publisher: Elsevier BV
Date: 2019
Cell Metabolism and DNA Repair Pathways: Implications for Cancer Therapy
Publisher: Frontiers Media SA
Date: 23-03-2021
DOI: 10.3389/FCELL.2021.633305
Abstract: DNA repair and metabolic pathways are vital to maintain cellular homeostasis in normal human cells. Both of these pathways, however, undergo extensive changes during tumorigenesis, including modifications that promote rapid growth, genetic heterogeneity, and survival. While these two areas of research have remained relatively distinct, there is growing evidence that the pathways are interdependent and intrinsically linked. Therapeutic interventions that target metabolism or DNA repair systems have entered clinical practice in recent years, highlighting the potential of targeting these pathways in cancer. Further exploration of the links between metabolic and DNA repair pathways may open new therapeutic avenues in the future. Here, we discuss the dependence of DNA repair processes upon cellular metabolism including the production of nucleotides required for repair, the necessity of metabolic pathways for the chromatin remodeling required for DNA repair, and the ways in which metabolism itself can induce and prevent DNA damage. We will also discuss the roles of metabolic proteins in DNA repair and, conversely, how DNA repair proteins can impact upon cell metabolism. Finally, we will discuss how further research may open therapeutic avenues in the treatment of cancer.
Single-stranded DNA-binding protein hSSB1 is critical for genomic stability
Publisher: Springer Science and Business Media LLC
Date: 30-04-2008
DOI: 10.1038/NATURE06883
Abstract: Single-strand DNA (ssDNA)-binding proteins (SSBs) are ubiquitous and essential for a wide variety of DNA metabolic processes, including DNA replication, recombination, DNA damage detection and repair. SSBs have multiple roles in binding and sequestering ssDNA, detecting DNA damage, stimulating nucleases, helicases and strand-exchange proteins, activating transcription and mediating protein-protein interactions. In eukaryotes, the major SSB, replication protein A (RPA), is a heterotrimer. Here we describe a second human SSB (hSSB1), with a domain organization closer to the archaeal SSB than to RPA. Ataxia telangiectasia mutated (ATM) kinase phosphorylates hSSB1 in response to DNA double-strand breaks (DSBs). This phosphorylation event is required for DNA damage-induced stabilization of hSSB1. Upon induction of DNA damage, hSSB1 accumulates in the nucleus and forms distinct foci independent of cell-cycle phase. These foci co-localize with other known repair proteins. In contrast to RPA, hSSB1 does not localize to replication foci in S-phase cells and hSSB1 deficiency does not influence S-phase progression. Depletion of hSSB1 abrogates the cellular response to DSBs, including activation of ATM and phosphorylation of ATM targets after ionizing radiation. Cells deficient in hSSB1 exhibit increased radiosensitivity, defective checkpoint activation and enhanced genomic instability coupled with a diminished capacity for DNA repair. These findings establish that hSSB1 influences erse endpoints in the cellular DNA damage response.
Substrate recognition and catalysis by the Holliday junction resolving enzyme Hje
Publisher: Oxford University Press (OUP)
Date: 11-10-2004
DOI: 10.1093/NAR/GKH869
Identification of Proteins Deregulated by Platinum-Based Chemotherapy as Novel Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer
Publisher: Frontiers Media SA
Date: 11-03-2021
Abstract: Platinum-based chemotherapy remains the cornerstone of treatment for most people with non-small cell lung cancer (NSCLC), either as adjuvant therapy in combination with a second cytotoxic agent or in combination with immunotherapy. Resistance to therapy, either in the form of primary refractory disease or evolutionary resistance, remains a significant issue in the treatment of NSCLC. Hence, predictive biomarkers and novel combinational strategies are required to improve the effectiveness and durability of treatment response 6for people with NSCLC. The aim of this study was to identify novel biomarkers and/or druggable proteins from deregulated protein networks within non-oncogene driven disease that are involved in the cellular response to cisplatin. Following exposure of NSCLC cells to cisplatin, in vitro quantitative mass spectrometry was applied to identify altered protein response networks. A total of 65 proteins were significantly deregulated following cisplatin exposure. These proteins were assessed to determine if they are druggable targets using novel machine learning approaches and to identify whether these proteins might serve as prognosticators of platinum therapy. Our data demonstrate novel candidates and drug-like molecules warranting further investigation to improve response to platinum agents in NSCLC.
Phosphorylation of Exo1 modulates homologous recombination repair of DNA double-strand breaks
Publisher: Oxford University Press (OUP)
Date: 24-02-2010
DOI: 10.1093/NAR/GKP1164
Recent advances in cancer therapy targeting proteins involved in DNA double-strand break repair
Publisher: American Association for Cancer Research (AACR)
Date: 14-10-2009
DOI: 10.1158/1078-0432.CCR-09-0096
Abstract: Damage to genetic material represents a persistent and ubiquitous threat to genomic stability. Once DNA damage is detected, a multifaceted signaling network is activated that halts the cell cycle, initiates repair, and in some instances induces apoptotic cell death. In this article, we will review DNA damage surveillance networks, which maintain the stability of our genome, and discuss the efforts underway to identify chemotherapeutic compounds targeting the core components of DNA double-strand breaks (DSB) response pathway. The majority of tumor cells have defects in maintaining genomic stability owing to the loss of an appropriate response to DNA damage. New anticancer agents are exploiting this vulnerability of cancer cells to enhance therapeutic indexes, with limited normal tissue toxicity. Recently inhibitors of the checkpoint kinases Chk1 and Chk2 have been shown to sensitize tumor cells to DNA damaging agents. In addition, the treatment of BRCA1- or BRCA2-deficient tumor cells with poly(ADP-ribose) polymerase (PARP) inhibitors also leads to specific tumor killing. Due to the numerous roles of p53 in genomic stability and its defects in many human cancers, therapeutic agents that restore p53 activity in tumors are the subject of multiple clinical trials. In this article we highlight the proteins mentioned above and catalog several additional players in the DNA damage response pathway, including ATM, DNA-PK, and the MRN complex, which might be amenable to pharmacological interventions and lead to new approaches to sensitize cancer cells to radio- and chemotherapy. The challenge is how to identify those patients most receptive to these treatments. (Clin Cancer Res 2009 (20):6314–20)
A novel corepressor, BCoR-L1, represses transcription through an interaction with CtBP.
Publisher: Elsevier BV
Date: 05-2007
Involvement of Exo1b in DNA damage-induced apoptosis
Publisher: Oxford University Press (OUP)
Date: 04-2009
DOI: 10.1093/NAR/GKP194
hSSB1 phosphorylation is dynamically regulated by DNA-PK and PPP-family protein phosphatases
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.DNAREP.2017.03.006
Abstract: The maintenance of genomic stability is essential for cellular viability and the prevention of diseases such as cancer. Human single-stranded DNA-binding protein 1 (hSSB1) is a protein with roles in the stabilisation and restart of stalled DNA replication forks, as well as in the repair of oxidative DNA lesions and double-strand DNA breaks. In the latter process, phosphorylation of threonine 117 by the ATM kinase is required for hSSB1 stability and efficient DNA repair. The regulation of hSSB1 in other DNA repair pathways has however remained unclear. Here we report that hSSB1 is also directly phosphorylated by DNA-PK at serine residue 134. While this modification is largely suppressed in undamaged cells by PPP-family protein phosphatases, S134 phosphorylation is enhanced following the disruption of replication forks and promotes cellular survival. Together, these data thereby represent a novel mechanism for hSSB1 regulation following the inhibition of replication.
High-Plex and High-throughput Digital Spatial Profiling of non-small-cell lung cancer (NSCLC)
Publisher: Cold Spring Harbor Laboratory
Date: 24-07-2020
DOI: 10.1101/2020.07.22.20160325
Abstract: Profiling the tumour microenvironment(TME) has been informative in understanding the underlying tumour-immune interactions. Multiplex immunohistochemistry(mIHC) coupled with molecular barcoding technologies have revealed greater insights into the TME. In this study, we utilised the Nanostring GeoMX™ Digital Spatial Profiler (DSP) platform to profile a NSCLC tissue microarray for protein markers across immune cell profiling, immuno-oncology(IO) drug target, immune activation status, immune cell typing, and pan-tumour protein modules. Regions of interest(ROIs) were selected that described tumour, TME and normal adjacent tissue(NAT) compartments. Our data revealed that paired analysis (n=18) of patient matched compartments indicated that the TME was significantly enriched in CD27, CD3, CD4, CD44, CD45, CD45RO, CD68, CD163, and VISTA relative to tumour. Unmatched analysis indicated that the NAT(n=19) was significantly enriched in CD34, fibronectin, IDO1, LAG3, ARG1 and PTEN when compared to the TME(n=32). Univariate Cox proportional hazards indicated that the presence of cells expressing CD3(HR:0.5, p=0.018), CD34(HR:0.53, p=0.004) and ICOS (HR:0.6, p=0.047) in tumour compartments were significantly associated with improved overall survival(OS). We implemented both high-plex and high-throughput methodologies to the discovery of protein biomarkers and molecular phenotypes within biopsy s les and demonstrate the power of such tools for a new generation of pathology research. The authors have declared that no conflict of interest exists.
P2.01-031 CCL Chemokines May Play an Important Role in Cisplatin Resistance
Publisher: Elsevier BV
Date: 2017
Circulating tumor cell clusters: Insights into tumour dissemination and metastasis.
Publisher: Informa UK Limited
Date: 11-2020
Assessing molecular docking tools to guide targeted drug discovery of cd38 inhibitors
Publisher: MDPI AG
Date: 22-07-2020
DOI: 10.3390/IJMS21155183
Abstract: A promising protein target for computational drug development, the human cluster of differentiation 38 (CD38), plays a crucial role in many physiological and pathological processes, primarily through the upstream regulation of factors that control cytoplasmic Ca2+ concentrations. Recently, a small-molecule inhibitor of CD38 was shown to slow down pathways relating to aging and DNA damage. We examined the performance of seven docking programs for their ability to model protein-ligand interactions with CD38. A test set of twelve CD38 crystal structures, containing crystallized biologically relevant substrates, were used to assess pose prediction. The rankings for each program based on the median RMSD between the native and predicted were Vina, AD4 PLANTS, Gold, Glide, Molegro rDock. Forty-two compounds with known affinities were docked to assess the accuracy of the programs at affinity/ranking predictions. The rankings based on scoring power were: Vina, PLANTS Glide, Gold Molegro AutoDock 4 rDock. Out of the top four performing programs, Glide had the only scoring function that did not appear to show bias towards overpredicting the affinity of the ligand-based on its size. Factors that affect the reliability of pose prediction and scoring are discussed. General limitations and known biases of scoring functions are examined, aided in part by using molecular fingerprints and Random Forest classifiers. This machine learning approach may be used to systematically diagnose molecular features that are correlated with poor scoring accuracy.
Deep Learning-Based Pan-Cancer Classification Model Reveals Tissue-of-Origin Specific Gene Expression Signatures
Publisher: MDPI AG
Date: 24-02-2022
Abstract: Cancer tissue-of-origin specific biomarkers are needed for effective diagnosis, monitoring, and treatment of cancers. In this study, we analyzed transcriptomics data from 37 cancer types provided by The Cancer Genome Atlas (TCGA) to identify cancer tissue-of-origin specific gene expression signatures. We developed a deep neural network model to classify cancers based on gene expression data. The model achieved a predictive accuracy of % across cancer types indicating the presence of distinct cancer tissue-of-origin specific gene expression signatures. We interpreted the model using Shapley additive explanations to identify specific gene signatures that significantly contributed to cancer-type classification. We evaluated the model and the validity of gene signatures using an independent test data set from the International Cancer Genome Consortium. In conclusion, we present a robust neural network model for accurate classification of cancers based on gene expression data and also provide a list of gene signatures that are valuable for developing biomarker panels for determining cancer tissue-of-origin. These gene signatures serve as valuable biomarkers for determining tissue-of-origin for cancers of unknown primary.
Identification of a BRCA1-mRNA Splicing Complex Required for Efficient DNA Repair and Maintenance of Genomic Stability
Publisher: Elsevier BV
Date: 05-2014
Targeting BRAF mutations in non-small cell lung cancer.
Publisher: AME Publishing Company
Date: 12-2019
P3.01-064 The Overexpression and Cleavage of SASH1 by Caspase-3 Stimulates Cell Death in Lung Cancer Cells
Publisher: Elsevier BV
Date: 2017
PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance
Publisher: Frontiers Media SA
Date: 09-09-2020
Contribution of DEAF1 structural domains to the interaction with the breast cancer oncogene LMO4
Publisher: Public Library of Science (PLoS)
Date: 19-06-2012
HSSB1 (NABP2/OBFC2B) is regulated by oxidative stress
Publisher: Springer Science and Business Media LLC
Date: 08-06-2016
DOI: 10.1038/SREP27446
Abstract: The maintenance of genome stability is an essential cellular process to prevent the development of diseases including cancer. hSSB1 (NABP2/ OBFC2A) is a critical component of the DNA damage response where it participates in the repair of double-strand DNA breaks and in base excision repair of oxidized guanine residues (8-oxoguanine) by aiding the localization of the human 8-oxoguanine glycosylase (hOGG1) to damaged DNA. Here we demonstrate that following oxidative stress, hSSB1 is stabilized as an oligomer which is required for hSSB1 to function in the removal of 8-oxoguanine. Monomeric hSSB1 shows a decreased affinity for oxidized DNA resulting in a cellular 8-oxoguanine-repair defect and in the absence of ATM signaling initiation. While hSSB1 oligomerization is important for the removal of 8-oxoguanine from the genome, it is not required for the repair of double-strand DNA-breaks by homologous recombination. These findings demonstrate a novel hSSB1 regulatory mechanism for the repair of damaged DNA.
Structure of Hjc, a Holliday junction resolvase, from Sulfolobus solfataricus
Publisher: Proceedings of the National Academy of Sciences
Date: 05-2001
Abstract: The 2.15-Å structure of Hjc, a Holliday junction-resolving enzyme from the archaeon Sulfolobus solfataricus , reveals extensive structural homology with a superfamily of nucleases that includes type II restriction enzymes. Hjc is a dimer with a large DNA-binding surface consisting of numerous basic residues surrounding the metal-binding residues of the active sites. Residues critical for catalysis, identified on the basis of sequence comparisons and site-directed mutagenesis studies, are clustered to produce two active sites in the dimer, about 29 Å apart, consistent with the requirement for the introduction of paired nicks in opposing strands of the four-way DNA junction substrate. Hjc displays similarity to the restriction endonucleases in the way its specific DNA-cutting pattern is determined but uses a different arrangement of nuclease subunits. Further structural similarity to a broad group of metal hosphate-binding proteins, including conservation of active-site location, is observed. A high degree of conservation of surface electrostatic character is observed between Hjc and T4-phage endonuclease VII despite a complete lack of structural homology. A model of the Hjc–Holliday junction complex is proposed, based on the available functional and structural data.
Epidermal Growth Factor potentiates EGFR(Y992/1173)-mediated therapeutic response of triple negative breast cancer cells to cold atmospheric plasma-activated medium
Publisher: Cold Spring Harbor Laboratory
Date: 02-06-2023
DOI: 10.1101/2023.05.30.542966
Abstract: Cold atmospheric plasma (CAP) holds promise as a cancer-specific treatment that selectively kills basal-like breast cancer cells. We used CAP-activated media (PAM) to capture the multi-modal chemical species of CAP. Specific antibodies, small molecule inhibitors and CRISPR/Cas9 gene-editing approaches showed an essential role for receptor tyrosine kinases, especially epidermal growth factor (EGF) receptor, in mediating triple negative breast cancer (TNBC) cell responses to PAM. EGF also dramatically enhanced the sensitivity and specificity of PAM against TNBC cells. Site-specific phospho-EGFR analysis, signal transduction inhibitors and reconstitution of EGFR-depleted cells with EGFR-mutants confirmed the role of phospho-tyrosines 992/1173 and phospholipase C gamma signaling in upregulating levels of reactive oxygen species above the apoptotic threshold. EGF-triggered EGFR activation enhanced the sensitivity and selectivity of PAM effects on TNBC cells, such that a strategy based on the synergism of CAP and EGF therapy may provide new opportunities to improve the clinical management of TNBC.
Programmed Death-1 Ligand 2-Mediated Regulation of the PD-L1 to PD-1 Axis Is Essential for Establishing CD4 + T Cell Immunity
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.IMMUNI.2016.07.017
Abstract: Many pathogens, including Plasmodium spp., exploit the interaction of programmed death-1 (PD-1) with PD-1-ligand-1 (PD-L1) to "deactivate" T cell functions, but the role of PD-L2 remains unclear. We studied malarial infections to understand the contribution of PD-L2 to immunity. Here we have shown that higher PD-L2 expression on blood dendritic cells, from Plasmodium falciparum-infected in iduals, correlated with lower parasitemia. Mechanistic studies in mice showed that PD-L2 was indispensable for establishing effective CD4(+) T cell immunity against malaria, because it not only inhibited PD-L1 to PD-1 activity but also increased CD3 and inducible co-stimulator (ICOS) expression on T cells. Importantly, administration of soluble multimeric PD-L2 to mice with lethal malaria was sufficient to dramatically improve immunity and survival. These studies show immuno-regulation by PD-L2, which has the potential to be translated into an effective treatment for malaria and other diseases where T cell immunity is ineffective or short-lived due to PD-1-mediated signaling.
Structural investigation of CDCA3‐Cdh1 protein–protein interactions using in vitro studies and molecular dynamics simulation
Publisher: Wiley
Date: 14-02-2023
DOI: 10.1002/PRO.4572
Abstract: The anaphase‐promoting complex/cyclosome (APC/C) ubiquitin ligase and its cofactor, Cdh1, regulate the expression of several cell‐cycle proteins and their functions during mitosis. Levels of the protein cell ision cycle‐associated protein 3 (CDCA3), which is functionally required for mitotic entry, are regulated by APC/C Cdh1 . CDCA3 is an intrinsically disordered protein and contains both C‐terminal KEN box and D‐box recognition motifs, enabling binding to Cdh1. Our previous findings demonstrate that CDCA3 has a phosphorylation‐dependent non‐canonical ABBA‐like motif within the linker region bridging these two recognition motifs and is required for efficient binding to Cdh1. Here, we sought to identify and further characterize additional residues that participate within this ABBA‐like motif using detailed in vitro experiments and in silico modeling studies. We identified the role of H‐bonds, hydrophobic and ionic interactions across the CDCA3 ABBA‐like motif in the linker region between KEN and D‐box motifs. This linker region adopts a well‐defined structure when bound to Cdh1 in the presence of phosphorylation. Upon alanine mutation, the structure of this region is lost, leading to higher flexibility, and alteration in affinities due to binding to alternate sites on Cdh1. Our findings identify roles for the anchoring residues in the non‐canonical ABBA‐like motif to promote binding to the APC/C Cdh1 and regulation of CDCA3 protein levels.
The fructose-bisphosphate, Aldolase A (ALDOA), facilitates DNA-PKcs and ATM kinase activity to regulate DNA double-strand break repair
Publisher: Springer Science and Business Media LLC
Date: 13-09-2023
Circulating tumour cells, their role in metastasis and their clinical utility in lung cancer
Publisher: Elsevier BV
Date: 04-2012
DOI: 10.1016/J.LUNGCAN.2011.10.018
Abstract: Circulating tumour cells (CTCs) have attracted much recent interest in cancer research as a potential biomarker and as a means of studying the process of metastasis. It has long been understood that metastasis is a hallmark of malignancy, and conceptual theories on the basis of metastasis from the nineteenth century foretold the existence of a tumour "seed" which is capable of establishing discrete tumours in the "soil" of distant organs. This prescient "seed and soil" hypothesis accurately predicted the existence of CTCs microscopic tumour fragments in the blood, at least some of which are capable of forming metastases. However, it is only in recent years that reliable, reproducible methods of CTC detection and analysis have been developed. To date, the majority of studies have employed the CellSearch™ system (Veridex LLC), which is an immunomagnetic purification method. Other promising techniques include microfluidic filters, isolation of tumour cells by size using microporous polycarbonate filters and flow cytometry-based approaches. While many challenges still exist, the detection of CTCs in blood is becoming increasingly feasible, giving rise to some tantalizing questions about the use of CTCs as a potential biomarker. CTC enumeration has been used to guide prognosis in patients with metastatic disease, and to act as a surrogate marker for disease response during therapy. Other possible uses for CTC detection include prognostication in early stage patients, identifying patients requiring adjuvant therapy, or in surveillance, for the detection of relapsing disease. Another exciting possible use for CTC detection assays is the molecular and genetic characterization of CTCs to act as a "liquid biopsy" representative of the primary tumour. Indeed it has already been demonstrated that it is possible to detect HER2, KRAS and EGFR mutation status in breast, colon and lung cancer CTCs respectively. In the course of this review, we shall discuss the biology of CTCs and their role in metastagenesis, the most commonly used techniques for their detection and the evidence to date of their clinical utility, with particular reference to lung cancer.
Human single-stranded DNA protein 1 (hSSB1): a prognostic factor and target for non-small cell lung cancer (NSCLC) treatment
Publisher: Elsevier BV
Date: 2019
The structural basis of DNA binding by the single-stranded DNA-binding protein from Sulfolobus solfataricus
Publisher: Portland Press Ltd.
Date: 06-01-2015
DOI: 10.1042/BJ20141140
Abstract: Canonical single-stranded DNA-binding proteins (SSBs) from the oligosaccharide/oligonucleotide-binding (OB) domain family are present in all known organisms and are critical for DNA replication, recombination and repair. The SSB from the hyperthermophilic crenarchaeote Sulfolobus solfataricus (SsoSSB) has a ‘simple’ domain organization consisting of a single DNA-binding OB fold coupled to a flexible C-terminal tail, in contrast with other SSBs in this family that incorporate up to four OB domains. Despite the large differences in the domain organization within the SSB family, the structure of the OB domain is remarkably similar all cellular life forms. However, there are significant differences in the molecular mechanism of ssDNA binding. We have determined the structure of the SsoSSB OB domain bound to ssDNA by NMR spectroscopy. We reveal that ssDNA recognition is modulated by base-stacking of three key aromatic residues, in contrast with the OB domains of human RPA and the recently discovered human homologue of SsoSSB, hSSB1. We also demonstrate that SsoSSB binds ssDNA with a footprint of five bases and with a defined binding polarity. These data elucidate the structural basis of DNA binding and shed light on the molecular mechanism by which these ‘simple’ SSBs interact with ssDNA.
Chemotherapeutic Compounds Targeting the DNA Double-Strand Break Repair Pathways: The Good, the Bad, and the Promising
Publisher: Frontiers Media SA
Date: 22-04-2014
Targeting NF-κB-mediated inflammatory pathways in cisplatin-resistant NSCLC
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.LUNGCAN.2019.07.006
Abstract: The majority of patients with non-small cell lung cancer (NSCLC) present with advanced stage disease, at which time chemotherapy is usually the most common treatment option. While somewhat effective, patients treated with platinum-based regimens will eventually develop resistance, with others presenting with intrinsic resistance. Multiple pathways have been implicated in chemo-resistance, however the critical underlying mechanisms have yet to be elucidated. The aim of this project was to determine the role of inflammatory mediators in cisplatin-resistance in NSCLC. Inflammatory mediator, NF-κB, and its associated pathways were investigated in an isogenic model of cisplatin-resistant NSCLC using age-matched parental (PT) and corresponding cisplatin-resistant (CisR) sublines. Pathways were assessed using mass spectrometry, western blot analysis and qRT-PCR. The cisplatin sensitizing potential of an NF-κB small molecule inhibitor, DHMEQ, was also assessed by means of viability assays and western blot analysis. Proteomic analysis identified dysregulated NF-κB responsive targets in CisR cells when compared to PT cells, with increased NF-κB expression identified in four out of the five NSCLC sub-types examined (CisR versus PT). DHMEQ treatment resulted in reduced NF-κB expression in the presence of cisplatin, and re-sensitized CisR cells to the cytotoxic effects of the drug. This study identified NF-ĸB as a potential therapeutic target in cisplatin-resistant NSCLC. Furthermore, inhibition of NF-ĸB using DHMEQ re-sensitized chemo-resistant cells to cisplatin treatment.
ATM mediated phosphorylation of CHD4 contributes to genome maintenance
Publisher: ScienceOpen
Date: 2011
The role of the immune microenvironment in EGFR mutant NSCLC
Publisher: Elsevier BV
Date: 06-2021
hSSB1 rapidly binds at the sites of DNA double-strand breaks and is required for the efficient recruitment of the MRN complex
Publisher: Oxford University Press (OUP)
Date: 03-11-2010
DOI: 10.1093/NAR/GKQ1098
Editorial: Mechanisms guarding the genome
Publisher: Frontiers Media SA
Date: 15-08-2022
Low frequency of CHEK2 1100delC allele in Australian multiple-case breast cancer families: functional analysis in heterozygous individuals
Publisher: Springer Science and Business Media LLC
Date: 02-2005
16P The overexpression of SASH1 stimulates cell death in lung cancer cells
Publisher: Elsevier BV
Date: 04-2016
Functions and therapeutic roles of exosomes in cancer
Publisher: Frontiers Media SA
Date: 27-05-2014
Senataxin controls meiotic silencing through ATR activation and chromatin remodeling
Publisher: Springer Science and Business Media LLC
Date: 29-09-2015
Abstract: Senataxin, defective in ataxia oculomotor apraxia type 2, protects the genome by facilitating the resolution of RNA–DNA hybrids (R-loops) and other aspects of RNA processing. Disruption of this gene in mice causes failure of meiotic recombination and defective meiotic sex chromosome inactivation, leading to male infertility. Here we provide evidence that the disruption of Setx leads to reduced SUMOylation and disruption of protein localization across the XY body during meiosis. We demonstrate that senataxin and other DNA damage repair proteins, including ataxia telangiectasia and Rad3-related protein-interacting partner, are SUMOylated, and a marked downregulation of both ataxia telangiectasia and Rad3-related protein-interacting partner and TopBP1 leading to defective activation and signaling through ataxia telangiectasia and Rad3-related protein occurs in the absence of senataxin. Furthermore, chromodomain helicase DNA-binding protein 4, a component of the nucleosome remodeling and deacetylase chromatin remodeler that interacts with both ataxia telangiectasia and Rad3-related protein and senataxin was not recruited efficiently to the XY body, triggering altered histone acetylation and chromatin conformation in Setx −/− pachytene-staged spermatocytes. These results demonstrate that senataxin has a critical role in ataxia telangiectasia and Rad3-related protein- and chromodomain helicase DNA-binding protein 4-mediated transcriptional silencing and chromatin remodeling during meiosis providing greater insight into its critical role in gene regulation to protect against neurodegeneration.
CDCA3 regulates the cell cycle and modulates cisplatin sensitivity in non-small cell lung cancer [Conference Abstract - ELCC 2016]
Publisher: Elsevier BV
Date: 04-2016
Mono-phosphorylation at Ser4 of barrier-to-autointegration factor (Banf1) significantly reduces its DNA binding capability by inducing critical changes in its local conformation and DNA binding surface
Publisher: Royal Society of Chemistry (RSC)
Date: 2023
DOI: 10.1039/D3CP02302H
Abstract: Barrier-to-Autointegration Factor (Banf1) is a small DNA-bridging protein. The binding status of Banf1 to DNA is regulated by its N-terminal phosphorylation and dephosphorylation, which plays a critical role in cell...
hSSB1 and hSSB2 Form Similar Multiprotein Complexes That Participate in DNA Damage Response
Publisher: Elsevier BV
Date: 08-2009
A biophysical and structural analysis of DNA binding by oligomeric hSSB1 (NABP2/OBFC2B)
Publisher: Cold Spring Harbor Laboratory
Date: 27-08-2020
DOI: 10.1101/2020.08.26.269084
Abstract: The oxidative modification of DNA can result in the loss of genome integrity and must be repaired to maintain overall genomic stability. We have recently demonstrated that human single stranded DNA binding protein 1 (hSSB1/NABP2/OBFC2B) plays a crucial role in the removal of 8-oxo-7,8-dihydro- guanine (8-oxoG), the most common form of oxidative DNA damage. The ability of hSSB1 to form disulphide-bonded tetramers and higher oligomers in an oxidative environment is critical for this process. In this study, we have used nuclear magnetic resonance (NMR) spectroscopy and surface plasmon resonance (SPR) experiments to determine the molecular details of ssDNA binding by oligomeric hSSB1. We reveal that hSSB1 oligomers interact with single DNA strands containing damaged DNA bases however, our data also show that oxidised bases are recognised in the same manner as undamaged DNA bases. We further demonstrate that oxidised hSSB1 interacts with ssDNA with a significantly higher affinity than its monomeric form confirming that oligomeric proteins such as tetramers can bind directly to ssDNA. NMR experiments provide evidence that oligomeric hSSB1 is able to bind longer ssDNA in both binding polarities using a distinct set of residues different to those of the related SSB from Escherichia coli .
Chloropyramine increases NSCLC sensitivity to cisplatin in a SASH1 dependent manner
Publisher: Elsevier BV
Date: 2019
Epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC)
Publisher: MDPI AG
Date: 25-09-2020
DOI: 10.3390/PH13100273
Abstract: Epidermal growth factor receptor (EGFR) mutations are the most common oncogenic drivers in non-small-cell lung cancer (NSCLC). Significant developments have taken place which highlight the differences in tumor biology that exist between the mutant and wild-type subtypes of NSCLC. Patients with advanced EGFR-mutant NSCLC have a variety of EGFR-targeting agents available proven to treat their disease. This has led to superior patient outcomes when used as a monotherapy over traditional cytotoxic systemic therapy. Attempts at combining EGFR agents with other anticancer systemic treatment options, such as chemotherapy, antiangiogenic agents, and immunotherapy, have shown varied outcomes. Currently, no specific combination stands out to cause a shift away from the use of single-agent EGFR inhibitors in the first-line setting. Similarly, adjuvant EGFR inhibitors, are yet to significantly add to patient overall survival if used at earlier timepoints in the disease course. Liquid biopsy is an evolving technology with potential promise of being incorporated into the management paradigm of this disease. Data are emerging to suggest that this technique may be capable of identifying early resistance mechanisms and consequential disease progression on the basis of the analysis of blood-based circulating tumor cells.
Circulating Tumor Cells in Metastatic Breast Cancer: From Genome Instability to Metastasis
Publisher: Frontiers Media SA
Date: 16-07-2020
Chemo-Radiative Stress of Plasma as a Modulator of Charge-Dependent Nanodiamond Cytotoxicity
Publisher: American Chemical Society (ACS)
Date: 15-09-2020
Abstract: Efficient and selective internalization of nanoscale diamonds (also termed nanodiamonds, NDs) by living cells is of fundamental importance for their bionanotechnological applications. The biocompatibility of NDs is well established and has been suggested to arise from the limited membrane perturbation during their cellular translocation. However, the latter may be affected when cells are subjected to external stress. This study shows that the oxidative stress generated by atmospheric pressure cold plasmas (APCP) alters cell sensitivity to NDs, and their cytotoxicity profile. Both positively and negatively charged NDs are nontoxic to cells, here
hSSB1 (NABP2/OBFC2B) modulates the DNA damage and androgen-induced transcriptional response in prostate cancer
Publisher: Wiley
Date: 22-02-2023
DOI: 10.1002/PROS.24496
Abstract: Activation and regulation of androgen receptor (AR) signaling and the DNA damage response impact the prostate cancer (PCa) treatment modalities of androgen deprivation therapy (ADT) and radiotherapy. Here, we have evaluated a role for human single‐strand binding protein 1 (hSSB1/NABP2) in modulation of the cellular response to androgens and ionizing radiation (IR). hSSB1 has defined roles in transcription and maintenance of genome stability, yet little is known about this protein in PCa. We correlated hSSB1 with measures of genomic instability across available PCa cases from The Cancer Genome Atlas (TCGA). Microarray and subsequent pathway and transcription factor enrichment analysis were performed on LNCaP and DU145 prostate cancer cells. Our data demonstrate that hSSB1 expression in PCa correlates with measures of genomic instability including multigene signatures and genomic scars that are reflective of defects in the repair of DNA double‐strand breaks via homologous recombination. In response to IR‐induced DNA damage, we demonstrate that hSSB1 regulates cellular pathways that control cell cycle progression and the associated checkpoints. In keeping with a role for hSSB1 in transcription, our analysis revealed that hSSB1 negatively modulates p53 and RNA polymerase II transcription in PCa. Of relevance to PCa pathology, our findings highlight a transcriptional role for hSSB1 in regulating the androgen response. We identified that AR function is predicted to be impacted by hSSB1 depletion, whereby this protein is required to modulate AR gene activity in PCa. Our findings point to a key role for hSSB1 in mediating the cellular response to androgen and DNA damage via modulation of transcription. Exploiting hSSB1 in PCa might yield benefits as a strategy to ensure a durable response to ADT and/or radiotherapy and improved patient outcomes.
MA 03.11 Targeting CDCA3 Enhances Sensitivity to Platinum-Based Chemotherapy in Non-Small Cell Lung Cancer
Publisher: Elsevier BV
Date: 11-2017
P1.02-010 Novel Role of hSSB2 in the Base Excision Repair Pathway (BER)
Publisher: Elsevier BV
Date: 11-2017
P2.03b-096 Utilization of a Novel 3D Culture Technology for the Assessment of Chemo-Resistance in Non-Small Cell Lung Cancer
Publisher: Elsevier BV
Date: 2017
P2.01-081 CDCA3 is a Novel Prognostic Cell Cycle Protein and Target for Therapy in Non-Small Cell Lung Cancer
Publisher: Elsevier BV
Date: 2017
The Impact of Rare Human Variants on Barrier-To-Auto-Integration Factor 1 (Banf1) Structure and Function
Publisher: Frontiers Media SA
Date: 08-11-2021
DOI: 10.3389/FCELL.2021.775441
Abstract: Barrier-to-Autointegration Factor 1 (Banf1/BAF) is a critical component of the nuclear envelope and is involved in the maintenance of chromatin structure and genome stability. Banf1 is a small DNA binding protein that is conserved amongst multicellular eukaryotes. Banf1 functions as a dimer, and binds non-specifically to the phosphate backbone of DNA, compacting the DNA in a looping process. The loss of Banf1 results in loss of nuclear envelope integrity and aberrant chromatin organisation. Significantly, mutations in Banf1 are associated with the severe premature ageing syndrome, Néstor–Guillermo Progeria Syndrome. Previously, rare human variants of Banf1 have been identified, however the impact of these variants on Banf1 function has not been explored. Here, using in silico modelling, biophysical and cell-based approaches, we investigate the effect of rare human variants on Banf1 structure and function. We show that these variants do not significantly alter the secondary structure of Banf1, but several single amino acid variants in the N- and C-terminus of Banf1 impact upon the DNA binding ability of Banf1, without altering Banf1 localisation or nuclear integrity. The functional characterisation of these variants provides further insight into Banf1 structure and function and may aid future studies examining the potential impact of Banf1 function on nuclear structure and human health.
SASH1 mediates sensitivity of breast cancer cells to chloropyramine and is associated with prognosis in breast cancer
Publisher: Impact Journals, LLC
Date: 14-09-2016
Rodent blood-stage Plasmodium survive in dendritic cells that infect naive mice
Publisher: Proceedings of the National Academy of Sciences
Date: 20-06-2011
Abstract: Plasmodium spp. parasites cause malaria in 300 to 500 million in iduals each year. Disease occurs during the blood-stage of the parasite's life cycle, where the parasite is thought to replicate exclusively within erythrocytes. Infected in iduals can also suffer relapses after several years, from Plasmodium vivax and Plasmodium ovale surviving in hepatocytes. Plasmodium falciparum and Plasmodium malariae can also persist after the original bout of infection has apparently cleared in the blood, suggesting that host cells other than erythrocytes (but not hepatocytes) may harbor these blood-stage parasites, thereby assisting their escape from host immunity. Using blood stage transgenic Plasmodium berghei -expressing GFP (PbGFP) to track parasites in host cells, we found that the parasite had a tropism for CD317 + dendritic cells. Other studies using confocal microscopy, in vitro cultures, and cell transfer studies showed that blood-stage parasites could infect, survive, and replicate within CD317 + dendritic cells, and that small numbers of these cells released parasites infectious for erythrocytes in vivo. These data have identified a unique survival strategy for blood-stage Plasmodium , which has significant implications for understanding the escape of Plasmodium spp. from immune-surveillance and for vaccine development.
The Cancer Stem-Cell Hypothesis: Its Emerging Role in Lung Cancer Biology and Its Relevance for Future Therapy
Publisher: Elsevier BV
Date: 12-2012
Combination Therapy With Histone Deacetylase Inhibitors (HDACi) for the Treatment of Cancer: Achieving the Full Therapeutic Potential of HDACi
Publisher: Frontiers Media SA
Date: 29-03-2018
hSSB2 (NABP1) is required for the recruitment of RPA during the cellular response to DNA UV damage
Publisher: Springer Science and Business Media LLC
Date: 12-10-2021
DOI: 10.1038/S41598-021-99355-0
Abstract: Maintenance of genomic stability is critical to prevent diseases such as cancer. As such, eukaryotic cells have multiple pathways to efficiently detect, signal and repair DNA damage. One common form of exogenous DNA damage comes from ultraviolet B (UVB) radiation. UVB generates cyclobutane pyrimidine dimers (CPD) that must be rapidly detected and repaired to maintain the genetic code. The nucleotide excision repair (NER) pathway is the main repair system for this type of DNA damage. Here, we determined the role of the human Single-Stranded DNA Binding protein 2, hSSB2, in the response to UVB exposure. We demonstrate that hSSB2 levels increase in vitro and in vivo after UVB irradiation and that hSSB2 rapidly binds to chromatin. Depletion of hSSB2 results in significantly decreased Replication Protein A (RPA32) phosphorylation and impaired RPA32 localisation to the site of UV-induced DNA damage. Delayed recruitment of NER protein Xeroderma Pigmentosum group C (XPC) was also observed, leading to increased cellular sensitivity to UVB. Finally, hSSB2 was shown to have affinity for single-strand DNA containing a single CPD and for duplex DNA with a two-base mismatch mimicking a CPD moiety. Altogether our data demonstrate that hSSB2 is involved in the cellular response to UV exposure.
Rearranged During Transfection Fusions in Non-Small Cell Lung Cancer
Publisher: MDPI AG
Date: 03-05-2019
Abstract: Identifying and targeting specific oncogenic drivers has become standard of care in the routine management of patients with lung cancer. Research is ongoing to expand the number of drug targets that can offer clinically meaningful outcomes. Rearranged during transfection (RET) fusions are the latest oncogenic driver alterations that show potential as a drug target. RET fusions occur in 1–2% of non-small cell lung cancer (NSCLC) cases. They are more commonly associated with younger age, female gender, non-smokers and Asian ethnicity. The RET kinase is abnormally activated through fusion with a partner protein such as KIF5B, CCDC6 or NCOA4. This leads to downstream intracellular signalling and enhancement of gene transcription and cell proliferation. The effectiveness of multi-kinase inhibitors in RET positive NSCLC has been explored in early phase and retrospective studies. From these studies, the most effective agents identified include cabozantanib and vandetanib. Overall response rates (ORR) vary from 18–47% across studies. In general, these agents have a manageable toxicity profile, although there are a number of off-target toxicities. Similar to the increased activity in ALK rearranged disease, pemetrexed has demonstrated superior response rates in this patient group and should be considered. Selective RET inhibitors, including LOXO-292 and BLU-667, are progressing in clinical trials. LOXO-292 has demonstrated an impressive ORR of 77% in RET positive solid tumours. It is anticipated this agent will be an effective targeted therapeutic option for patients with RET positive lung cancer.
DNA repair pathways and their therapeutic potential in lung cancer
Publisher: Future Medicine Ltd
Date: 04-2014
DOI: 10.2217/LMT.14.12
Abstract: SUMMARY: Lung cancer is the leading cause of cancer-related mortality. According to WHO, 1.37 million deaths occur globally each year as a result of this disease. More than 70% of these cases are associated with prior tobacco consumption and/or cigarette smoking, suggesting a direct causal relationship. The development and progression of lung cancer and other malignancies involves the loss of genetic stability, resulting in acquisition of cumulative genetic changes this affords the cell increased malignant potential. As such, an understanding of the mechanisms through which these events may occur will potentially allow for development of new anticancer therapies. This review will address the association between lung cancer and genetic instability, with a central focus on genetic mutations in the DNA damage repair pathways. In addition, we will discuss the potential clinical exploitation of these pathways, both in terms of biomarker staging, as well as through direct therapeutic targeting.
A data-driven structural model of hSSB1 (NABP2/OBFC2B) self-oligomerization
Publisher: Oxford University Press (OUP)
Date: 13-06-2017
DOI: 10.1093/NAR/GKX526
Conformational flexibility revealed by the crystal structure of a crenarchaeal RadA
Publisher: Oxford University Press (OUP)
Date: 08-03-2005
DOI: 10.1093/NAR/GKI288
Vascular endothelial growth factor is an autocrine growth factor, signaling through neuropilin-1 in non-small cell lung cancer
Publisher: Springer Science and Business Media LLC
Date: 20-02-2015
Activation and cleavage of SASH1 by caspase-3 mediates an apoptotic response
Publisher: Springer Science and Business Media LLC
Date: 10-11-2016
Abstract: Apoptosis is a highly regulated cellular process that functions to remove undesired cells from multicellular organisms. This pathway is often disrupted in cancer, providing tumours with a mechanism to avoid cell death and promote growth and survival. The putative tumour suppressor, SASH1 (SAM and SH3 domain containing protein 1), has been previously implicated in the regulation of apoptosis however, the molecular role of SASH1 in this process is still unclear. In this study, we demonstrate that SASH1 is cleaved by caspase-3 following UVC-induced apoptosis. Proteolysis of SASH1 enables the C-terminal fragment to translocate from the cytoplasm to the nucleus where it associates with chromatin. The overexpression of wild-type SASH1 or a cleaved form of SASH1 representing amino acids 231–1247 leads to an increase in apoptosis. Conversely, mutation of the SASH1 cleavage site inhibits nuclear translocation and prevents the initiation of apoptosis. SASH1 cleavage is also required for the efficient translocation of the transcription factor nuclear factor- κ B (NF- κ B) to the nucleus. The use of the NF- κ B inhibitor DHMEQ demonstrated that the effect of SASH1 on apoptosis was dependent on NF- κ B, indicating a codependence between SASH1 and NF- κ B for this process.
Phytoremediation of Cadmium-Polluted Water/Sediment by Aquatic Macrophytes: Role of Plant-Induced pH Changes
Publisher: Elsevier
Date: 2019
Advances in hormonal therapies for hormone naïve and castration-resistant prostate cancers with or without previous chemotherapy.
Publisher: Springer Science and Business Media LLC
Date: 12-2015
Examination of EXOSC4 as a new prognostic marker and a novel therapeutic avenue in lung adenocarcinoma [Conference Abstract- ELCC 2016]
Publisher: Elsevier BV
Date: 04-2016
The Therapeutic Potential of DNA Damage Repair Pathways and Genomic Stability in Lung Cancer
Publisher: Frontiers Media SA
Date: 28-07-2020
Barrier-to-autointegration-factor (Banf1) modulates DNA double-strand break repair pathway choice via regulation of DNA-dependent kinase (DNA-PK) activity
Publisher: Oxford University Press (OUP)
Date: 28-02-2021
DOI: 10.1093/NAR/GKAB110
Abstract: DNA repair pathways are essential to maintain the integrity of the genome and prevent cell death and tumourigenesis. Here, we show that the Barrier-to-Autointegration Factor (Banf1) protein has a role in the repair of DNA double-strand breaks. Banf1 is characterized as a nuclear envelope protein and mutations in Banf1 are associated with the severe premature aging syndrome, Néstor–Guillermo Progeria Syndrome. We have previously shown that Banf1 directly regulates the activity of PARP1 in the repair of oxidative DNA lesions. Here, we show that Banf1 also has a role in modulating DNA double-strand break repair through regulation of the DNA-dependent Protein Kinase catalytic subunit, DNA-PKcs. Specifically, we demonstrate that Banf1 relocalizes from the nuclear envelope to sites of DNA double-strand breaks. We also show that Banf1 can bind to and directly inhibit the activity of DNA-PKcs. Supporting this, cellular depletion of Banf1 leads to an increase in non-homologous end-joining and a decrease in homologous recombination, which our data suggest is likely due to unrestrained DNA-PKcs activity. Overall, this study identifies how Banf1 regulates double-strand break repair pathway choice by modulating DNA-PKcs activity to control genome stability within the cell.
Drug Discovery Approaches Utilizing Three-Dimensional Cell Culture
Publisher: Mary Ann Liebert Inc
Date: 02-2016
DOI: 10.1089/ADT.2015.670
Abstract: Historically, two-dimensional (2D) cell culture has been the preferred method of producing disease models in vitro. Recently, there has been a move away from 2D culture in favor of generating three-dimensional (3D) multicellular structures, which are thought to be more representative of the in vivo environment. This transition has brought with it an influx of technologies capable of producing these structures in various ways. However, it is becoming evident that many of these technologies do not perform well in automated in vitro drug discovery units. We believe that this is a result of their incompatibility with high-throughput screening (HTS). In this study, we review a number of technologies, which are currently available for producing in vitro 3D disease models. We assess their amenability with high-content screening and HTS and highlight our own work in attempting to address many of the practical problems that are h ering the successful deployment of 3D cell systems in mainstream research.
Deep learning-based pan-cancer classification model reveals cancer-specific gene expression signatures
Publisher: Cold Spring Harbor Laboratory
Date: 18-03-2021
DOI: 10.1101/2021.03.15.435283
Abstract: The identification of cancer-specific biomarkers and therapeutic targets is one of the primary goals of cancer genomics. Thousands of cancer genomes, exomes, and transcriptomes have been sequenced to date. In this study, we conducted a pan-cancer analysis of transcriptome datasets from 37 cancer types provided by The Cancer Genome Atlas (TCGA) in an effort to identify cancer-specific gene expression signatures. We employed deep neural networks to train a model on the transcriptome profile datasets for all cancer types. The model was validated, and its predictive accuracy was determined using an independent dataset, achieving 97% prediction accuracy across cancer types. This strongly suggests that there are distinct gene expression signatures associated with various cancer types. We interpreted the model using SHapley Additive exPlanations (SHAP) to identify specific gene signatures that significantly contributed to the classification of cancer types. In addition to known biomarkers, we identified several novel biomarkers in different cancer types. These cancer-specific gene signatures are valuable candidates for future studies of their potential utility as cancer biomarkers and putative therapeutic targets.
Cold atmospheric plasma for preventing infection of viruses that use ACE2 for entry
Publisher: Ivyspring International Publisher
Date: 2022
DOI: 10.7150/THNO.70098
Modélisation de la clairance du 5-FU pendant une perfusion chronomodulée
Publisher: Elsevier BV
Date: 06-2003
DOI: 10.1016/S0369-8114(03)00039-7
Abstract: Drugs pharmacokinetic control is a usual practice in case of flat continuous infusions. It enables among others, to modulate delivered doses when drug concentrations in blood appear too high. With chronotherapy, this possibility becomes more difficult because of sinusoidal outflows of infusion. We propose here a method that enables this follow-up, established through the study of 21 metastatic colorectal cancer patients, treated with a chronomodulated infusion of high dose 5-fluoro-uracil (5-FU) and folinic acid. This pharmacokinetic follow-up permitted the modelisation of 5-FU clearance and the calculation of an index, which was, in our study, correlated to the treatment response and also to main encountered toxicities.
INTS3 controls the hSSB1-mediated DNA damage response
Publisher: Rockefeller University Press
Date: 28-09-2009
Abstract: Human SSB1 (single-stranded binding protein 1 [hSSB1]) was recently identified as a part of the ataxia telangiectasia mutated (ATM) signaling pathway. To investigate hSSB1 function, we performed tandem affinity purifications of hSSB1 mutants mimicking the unphosphorylated and ATM-phosphorylated states. Both hSSB1 mutants copurified a subset of Integrator complex subunits and the uncharacterized protein LOC58493/c9orf80 (henceforth minute INTS3/hSSB-associated element [MISE]). The INTS3–MISE–hSSB1 complex plays a key role in ATM activation and RAD51 recruitment to DNA damage foci during the response to genotoxic stresses. These effects on the DNA damage response are caused by the control of hSSB1 transcription via INTS3, demonstrating a new network controlling hSSB1 function.
INT6/EIF3E Interacts with ATM and Is Required for Proper Execution of the DNA Damage Response in Human Cells
Publisher: American Association for Cancer Research (AACR)
Date: 15-04-2012
DOI: 10.1158/0008-5472.CAN-11-2562
Abstract: Altered expression of the INT6 gene, encoding the e subunit of the translational initiation factor eIF3, occurs in human breast cancers, but how INT6 relates to carcinogenesis remains unestablished. Here, we show that INT6 is involved in the DNA damage response. INT6 was required for cell survival following γ-irradiation and G2–M checkpoint control. RNA interference–mediated silencing of INT6 reduced phosphorylation of the checkpoint kinases CHK1 and CHK2 after DNA damage. In addition, INT6 silencing prevented sustained accumulation of ataxia telangiectasia mutated (ATM) at DNA damage sites in cells treated with γ-radiation or the radiomimetic drug neocarzinostatin. Mechanistically, this result could be explained by interaction of INT6 with ATM, which together with INT6 was recruited to the sites of DNA damage. Finally, INT6 silencing also reduced ubiquitylation events that promote retention of repair proteins at DNA lesions. Accordingly, accumulation of the repair factor BRCA1 was defective in the absence of INT6. Our findings reveal unexpected and striking connections of INT6 with ATM and BRCA1 and suggest that the protective action of INT6 in the onset of breast cancers relies on its involvement in the DNA damage response. Cancer Res 72(8) 2006–16. ©2012 AACR.
Defining COMMD4 as an anti-cancer therapeutic target and potential diagnostic biomarker in lung cancer
Publisher: Elsevier BV
Date: 2019
67P Investigation of the interaction between non-small cell lung cancer cells and immortalised normal bronchial epithelial cells
Publisher: Elsevier BV
Date: 04-2016
Epithelial-to-mesenchymal transition enhances cancer cell sensitivity to cytotoxic effects of zcold atmospheric plasmas in breast and bladder cancer systems
Publisher: MDPI AG
Date: 09-06-2021
Abstract: Cold atmospheric plasma (CAP) has emerged as a highly selective anticancer agent, most recently in the form of plasma-activated medium (PAM). Since epithelial–mesenchymal transition (EMT) has been implicated in resistance to various cancer therapies, we assessed whether EMT status is associated with PAM response. Mesenchymal breast cancer cell lines, as well as the mesenchymal variant in an isogenic EMT/MET human breast cancer cell system (PMC42-ET/LA), were more sensitive to PAM treatment than their epithelial counterparts, contrary to their responses to other therapies. The same trend was seen in luminal muscle-invasive bladder cancer model (TSU-Pr1/B1/B2) and the non-muscle-invasive basal 5637 bladder cancer cell line. Three-dimensional spheroid cultures of the bladder cancer cell lines were less sensitive to the PAM treatment compared to their two-dimensional counterparts however, incrementally better responses were again seen in more mesenchymally-shifted cell lines. This study provides evidence that PAM preferentially inhibits mesenchymally-shifted carcinoma cells, which have been associated with resistance to other therapies. Thus, PAM may represent a novel treatment that can selectively inhibit triple-negative breast cancers and a subset of aggressive bladder cancers, which tend to be more mesenchymal. Our approach may potentially be utilized for other aggressive cancers exhibiting EMT and opens new opportunities for CAP and PAM as a promising new onco-therapy.
3 Chromosomal and mutational analysis of the cisplatin resistant phenotype in NSCLC
Publisher: Elsevier BV
Date: 2014
Nucleolar caspase-2: Protecting us from DNA damage
Publisher: Rockefeller University Press
Date: 12-05-2017
Abstract: Caspase-2 triggers apoptosis, but how it is activated by different stimuli is unclear. In this issue, Ando et al. (2017. J. Cell Biol. 0.1083/jcb.201608095) delineate two pathways of caspase-2 activation and show that, in response to DNA damage, caspase-2 forms a complex with the PIDDosome and NPM1 within the nucleolus.
Related Organisations
University Of Dundee
Location: United Kingdom of Great Britain and Northern Ireland
University Of St Andrews
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
ARC Future Fellowships - Grant ID: FT0991671
Start Date: 2010
End Date: 12-2014
Amount: $686,400.00
Funder: Australian Research Council
View Funded ActivityLinkage Infrastructure, Equipment And Facilities - Grant ID: LE180100179
Start Date: 03-2018
End Date: 12-2019
Amount: $3,189,000.00
Funder: Australian Research Council
View Funded ActivityLinkage Infrastructure, Equipment And Facilities - Grant ID: LE170100206
Start Date: 05-2017
End Date: 12-2017
Amount: $550,000.00
Funder: Australian Research Council
View Funded ActivityDiscovery Projects - Grant ID: DP120103099
Start Date: 2012
End Date: 12-2014
Amount: $295,000.00
Funder: Australian Research Council
View Funded Activity