ORCID Profile
0000-0002-5345-5741
Current Organisations
University of Sydney
,
Children's Medical Research Institute
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Springer Science and Business Media LLC
Date: 19-02-2015
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.PBIOMOLBIO.2019.04.002
Abstract: DNA replication plays a central role in genome health. Deleterious alteration of replication dynamics, or "replication stress", is a key driver of genome instability and oncogenesis. The replication stress response is regulated by the ATR kinase, which functions to mitigate replication abnormalities through coordinated efforts that arrest the cell cycle and repair damaged replication forks. mTOR kinase regulates signaling networks that control cell growth and metabolism in response to environmental cues and cell stress. In this review, we discuss interconnectivity between the ATR and mTOR pathways, and provide putative mechanisms for mTOR engagement in DNA replication and the replication stress response. Finally, we describe how connectivity between mTOR and replication stress may be exploited for cancer therapy.
Publisher: Springer Science and Business Media LLC
Date: 05-06-2017
DOI: 10.1038/ONC.2017.173
Publisher: The Company of Biologists
Date: 2016
DOI: 10.1242/JCS.179754
Abstract: Entry into mitosis is driven by the phosphorylation of thousands of substrates, under the master control of Cdk1. During entry into mitosis, Cdk1, in collaboration with MASTL kinase, represses the activity of the major mitotic protein phosphatases, PP1 and PP2A, thereby ensuring mitotic substrates remain phosphorylated. For cells to complete and exit mitosis, these phosphorylation events must be removed, and hence, phosphatase activity must be reactivated. This reactivation of phosphatase activity presumably requires the inhibition of MASTL, however, it is not currently understood how or what deactivates MASTL. In this study, we identified that PP1 is associated with and capable of partially dephosphorylating and deactivating MASTL during mitotic exit. Using mathematical modelling we were able to confirm that deactivation of MASTL is essential for mitotic exit. Furthermore, small decreases in Cdk1 activity during metaphase are sufficient to initiate the reactivation of PP1, which in turn partially deactivates MASTL to release inhibition of PP2A and hence create a feedback loop. This feedback loop drives complete deactivation of MASTL, ensuring a robust switch-like activation of phosphatase activity during mitotic exit.
Publisher: Frontiers Media SA
Date: 04-06-2014
Publisher: Informa UK Limited
Date: 06-03-2014
DOI: 10.4161/CC.28401
Publisher: Wiley
Date: 07-2016
Abstract: Entry into mitosis is driven by the activity of kinases, which phosphorylate over 7000 proteins on multiple sites. For cells to exit mitosis and segregate their genome correctly, these phosphorylations must be removed in a specific temporal order. This raises a critical and important question: how are specific phosphorylation sites on an in idual protein removed? Traditionally, the temporal order of dephosphorylation was attributed to decreasing kinase activity. However, recent evidence in human cells has identified unique patterns of dephosphorylation during mammalian mitotic exit that cannot be fully explained by the loss of kinase activity. This suggests that specificity is determined in part by phosphatases. In this review, we explore how the physicochemical properties of an in idual phosphosite and its surrounding amino acids can affect interactions with a phosphatase. These positive and negative interactions in turn help determine the specific pattern of dephosphorylation required for correct mitotic exit.
Publisher: Springer Science and Business Media LLC
Date: 16-11-2017
DOI: 10.1038/S41598-017-15885-6
Abstract: Quantification of cellular antigens and their interactions via antibody-based detection methods are widely used in scientific research. Accurate high-throughput quantitation of these assays using general image analysis software can be time consuming and challenging, particularly when attempted by users with limited image processing and analysis knowledge. To overcome this, we have designed Andy’s Algorithms, a series of automated image analysis pipelines for FIJI, that permits rapid, accurate and reproducible batch-processing of 3,3 ′ -diaminobenzidine (DAB) immunohistochemistry, proximity ligation assays (PLAs) and other common assays. Andy’s Algorithms incorporates a step-by-step tutorial and optimization pipeline to make batch image analysis simple for the untrained user and adaptable across laboratories. Andy’s algorithms provide a simpler, faster, standardized work flow compared to existing programs, while offering equivalent performance and additional features, in a free to use open-source application of FIJI. Andy’s Algorithms are available at GitHub, publicly accessed at ndlaw1841/Andy-s-Algorithm .
Publisher: Springer Science and Business Media LLC
Date: 17-02-2021
DOI: 10.1186/S13148-021-01023-7
Abstract: BRG1 (encoded by SMARCA4 ) is a catalytic component of the SWI/SNF chromatin remodelling complex, with key roles in modulating DNA accessibility. Dysregulation of BRG1 is observed, but functionally uncharacterised, in a wide range of malignancies. We have probed the functions of BRG1 on a background of prostate cancer to investigate how BRG1 controls gene expression programmes and cancer cell behaviour. Our investigation of SMARCA4 revealed that BRG1 is over-expressed in the majority of the 486 tumours from The Cancer Genome Atlas prostate cohort, as well as in a complementary panel of 21 prostate cell lines. Next, we utilised a temporal model of BRG1 depletion to investigate the molecular effects on global transcription programmes. Depleting BRG1 had no impact on alternative splicing and conferred only modest effect on global expression. However, of the transcriptional changes that occurred, most manifested as down-regulated expression. Deeper examination found the common thread linking down-regulated genes was involvement in proliferation, including several known to increase prostate cancer proliferation ( KLK2 , PCAT1 and VAV3 ). Interestingly, the promoters of genes driving proliferation were bound by BRG1 as well as the transcription factors, AR and FOXA1. We also noted that BRG1 depletion repressed genes involved in cell cycle progression and DNA replication, but intriguingly, these pathways operated independently of AR and FOXA1. In agreement with transcriptional changes, depleting BRG1 conferred G1 arrest. Our data have revealed that BRG1 promotes cell cycle progression and DNA replication, consistent with the increased cell proliferation associated with oncogenesis.
Publisher: Cold Spring Harbor Laboratory
Date: 13-05-2022
DOI: 10.1101/2022.05.12.491744
Abstract: Replication stress is an endemic threat to genome stability. For reasons unknown, replication stress response factors become essential during peri-implantation development. This coincides with a stem cell potency switch from the naïve to the primed state. Using genetically matched, chimera-derived mouse naïve embryonic (mESC) and primed epiblast stem cells (mEpiSC) we found that replication stress management differs between potency states. Primed mEpiSCs rely on Atr activity to prevent replication catastrophe, minimize genomic damage, avoid apoptosis, and re-enter the cell cycle. Conversely, under replications stress, mESCs readily activate Atm regardless of Atr activity, undergo replication catastrophe, and induce apoptosis. Primed pluripotent cells therefore engage Atr to counteract replication difficulties and maintain viability, whereas cells in the naïve state are more readily cleared under the same conditions. We anticipate these ergent strategies enable pluripotent cells of different potency states to meet associated proliferative or developmental demands during early development.
Publisher: Springer Science and Business Media LLC
Date: 10-05-2018
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.CELL.2017.06.003
Abstract: During mitosis, a cell ides its duplicated genome into two identical daughter cells. This process must occur without errors to prevent proliferative diseases (e.g., cancer). A key mechanism controlling mitosis is the precise timing of more than 32,000 phosphorylation and dephosphorylation events by a network of kinases and counterbalancing phosphatases. The identity, magnitude, and temporal regulation of these events have emerged recently, largely from advances in mass spectrometry. Here, we show phosphoevents currently believed to be key regulators of mitosis. For an animated version of this SnapShot, please see ell/enhanced/odonoghue2.
Publisher: Elsevier BV
Date: 12-2015
Publisher: MDPI AG
Date: 13-08-2020
Abstract: Genome doubling is an underlying cause of cancer cell aneuploidy and genomic instability, but few drivers have been identified for this process. Due to their physiological roles in the genome reduplication of normal cells, we hypothesised that the oncogenes cyclins E1 and E2 may be drivers of genome doubling in cancer. We show that both cyclin E1 (CCNE1) and cyclin E2 (CCNE2) mRNA are significantly associated with high genome ploidy in breast cancers. By live cell imaging and flow cytometry, we show that cyclin E2 overexpression promotes aberrant mitosis without causing mitotic slippage, and it increases ploidy with negative feedback on the replication licensing protein, Cdt1. We demonstrate that cyclin E2 localises with core preRC (pre-replication complex) proteins (MCM2, MCM7) on the chromatin of cancer cells. Low CCNE2 is associated with improved overall survival in breast cancers, and we demonstrate that low cyclin E2 protects from excess genome rereplication. This occurs regardless of p53 status, consistent with the association of high cyclin E2 with genome doubling in both p53 null/mutant and p53 wildtype cancers. In contrast, while cyclin E1 can localise to the preRC, its downregulation does not prevent rereplication, and overexpression promotes polyploidy via mitotic slippage. Thus, in breast cancer, cyclin E2 has a strong association with genome doubling, and likely contributes to highly proliferative and genomically unstable breast cancers.
Publisher: Elsevier BV
Date: 08-2015
Publisher: Elsevier BV
Date: 10-2021
DOI: 10.1016/J.TCB.2021.06.002
Abstract: The nucleus is a dynamic environment containing chromatin, membraneless organelles, and specialized molecular structures at the nuclear membrane. Within the spectrum of DNA repair activities are observations of increased mobility of damaged chromatin and the displacement of DNA lesions to specific nuclear environments. Here, we focus on the role that nuclear-specific filamentous actin plays in mobilizing damaged chromatin in response to DNA double-strand breaks and replication stress. We also examine nuclear pore complexes and promyelocytic leukemia-nuclear bodies as specialized platforms for homology-directed repair. The literature suggests an emerging model where specific types of DNA lesions are subjected to nuclear-derived forces that mobilize damaged chromatin and promote interaction with repair hubs to facilitate specialized repair reactions.
No related grants have been discovered for Samuel Rogers.