ORCID Profile
0000-0003-4176-1685
Current Organisations
City, University of London
,
University of Bristol
,
University of York
,
University of Zurich
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Publications
A low-complexity region in human XRN1 directly recruits deadenylation and decapping factors in 5′–3′ messenger RNA decay
Publisher: Oxford University Press (OUP)
Date: 24-07-2019
DOI: 10.1093/NAR/GKZ633
Abstract: XRN1 is the major cytoplasmic exoribonuclease in eukaryotes, which degrades deadenylated and decapped mRNAs in the last step of the 5′–3′ mRNA decay pathway. Metazoan XRN1 interacts with decapping factors coupling the final stages of decay. Here, we reveal a direct interaction between XRN1 and the CCR4–NOT deadenylase complex mediated by a low-complexity region in XRN1, which we term the ‘C-terminal interacting region’ or CIR. The CIR represses reporter mRNA deadenylation in human cells when overexpressed and inhibits CCR4–NOT and isolated CAF1 deadenylase activity in vitro. Through complementation studies in an XRN1-null cell line, we dissect the specific contributions of XRN1 domains and regions toward decay of an mRNA reporter. We observe that XRN1 binding to the decapping activator EDC4 counteracts the dominant negative effect of CIR overexpression on decay. Another decapping activator PatL1 directly interacts with CIR and alleviates the CIR-mediated inhibition of CCR4–NOT activity in vitro. Ribosome profiling revealed that XRN1 loss impacts not only on mRNA levels but also on the translational efficiency of many cellular transcripts likely as a consequence of incomplete decay. Our findings reveal an additional layer of direct interactions in a tightly integrated network of factors mediating deadenylation, decapping and 5′–3′ exonucleolytic decay.
4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA Decay
Publisher: Elsevier BV
Date: 10-2020
Structural motifs in eIF4G and 4E-BPs modulate their binding to eIF4E to regulate translation initiation in yeast
Publisher: Oxford University Press (OUP)
Date: 21-06-2018
DOI: 10.1093/NAR/GKY542
DAP5 enables main ORF translation on mRNAs with structured and uORF-containing 5′ leaders
Publisher: Springer Science and Business Media LLC
Date: 06-12-2022
DOI: 10.1038/S41467-022-35019-5
Abstract: Half of mammalian transcripts contain short upstream open reading frames (uORFs) that potentially regulate translation of the downstream coding sequence (CDS). The molecular mechanisms governing these events remain poorly understood. Here, we find that the non-canonical initiation factor Death-associated protein 5 (DAP5 or eIF4G2) is required for translation initiation on select transcripts. Using ribosome profiling and luciferase-based reporters coupled with mutational analysis we show that DAP5-mediated translation occurs on messenger RNAs (mRNAs) with long, structure-prone 5′ leader sequences and persistent uORF translation. These mRNAs preferentially code for signalling factors such as kinases and phosphatases. We also report that cap/eIF4F- and eIF4A-dependent recruitment of DAP5 to the mRNA facilitates main CDS, but not uORF, translation suggesting a role for DAP5 in translation re-initiation. Our study reveals important mechanistic insights into how a non-canonical translation initiation factor involved in stem cell fate shapes the synthesis of specific signalling factors.
The Structures of eIF4E-eIF4G Complexes Reveal an Extended Interface to Regulate Translation Initiation
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.MOLCEL.2016.09.020
Abstract: Eukaryotic initiation factor 4G (eIF4G) plays a central role in translation initiation through its interactions with the cap-binding protein eIF4E. This interaction is a major drug target for repressing translation and is naturally regulated by 4E-binding proteins (4E-BPs). 4E-BPs and eIF4G compete for binding to the eIF4E dorsal surface via a shared canonical 4E-binding motif, but also contain auxiliary eIF4E-binding sequences, which were assumed to contact non-overlapping eIF4E surfaces. However, it is unknown how metazoan eIF4G auxiliary sequences bind eIF4E. Here, we describe crystal structures of human and Drosophila melanogaster eIF4E-eIF4G complexes, which unexpectedly reveal that the eIF4G auxiliary sequences bind to the lateral surface of eIF4E, using a similar mode to that of 4E-BPs. Our studies provide a molecular model of the eIF4E-eIF4G complex, shed light on the competition mechanism of 4E-BPs, and enable the rational design of selective eIF4G inhibitors to d en dysregulated translation in disease.
GIGYF1/2 proteins use auxiliary sequences to selectively bind to 4EHP and repress target mRNA expression
Publisher: Cold Spring Harbor Laboratory
Date: 06-2017
Abstract: The eIF4E homologous protein (4EHP) is thought to repress translation by competing with eIF4E for binding to the 5′ cap structure of specific mRNAs to which it is recruited through interactions with various proteins, including the GRB10-interacting GYF (glycine–tyrosine–phenylalanine domain) proteins 1 and 2 (GIGYF1/2). Despite its similarity to eIF4E, 4EHP does not interact with eIF4G and therefore fails to initiate translation. In contrast to eIF4G, GIGYF1/2 bind selectively to 4EHP but not eIF4E. Here, we present crystal structures of the 4EHP-binding regions of GIGYF1 and GIGYF2 in complex with 4EHP, which reveal the molecular basis for the selectivity of the GIGYF1/2 proteins for 4EHP. Complementation assays in a GIGYF1/2-null cell line using structure-based mutants indicate that 4EHP requires interactions with GIGYF1/2 to down-regulate target mRNA expression. Our studies provide structural insights into the assembly of 4EHP–GIGYF1/2 repressor complexes and reveal that rather than merely facilitating 4EHP recruitment to transcripts, GIGYF1/2 proteins are required for repressive activity.
DAP5 enables translation re-initiation on structured messenger RNAs
Publisher: Cold Spring Harbor Laboratory
Date: 21-01-2021
DOI: 10.1101/2021.01.21.427569
Abstract: Half of mammalian transcripts contain short upstream open reading frames (uORFs) that potentially regulate translation of the downstream coding sequence (CDS). The molecular mechanisms governing these events remain poorly understood. Here we find that the non-canonical initiation factor Death-associated protein 5 (DAP5 or eIF4G2) is selectively required for re-initiation at the main CDS following uORF translation. Using ribosome profiling and luciferase-based reporters coupled with mutational analysis we show that DAP5-mediated re-initiation occurs on messenger RNAs (mRNAs) with long, structure-prone 5′ leader sequences and persistent uORF translation. These mRNAs preferentially code for signalling factors such as kinases and phosphatases. We also report that cap/eIF4F- and eIF4A-dependent recruitment of DAP5 to the mRNA facilitates re-initiation by unrecycled post-termination 40S subunits. Our study reveals important mechanistic insights into how a non-canonical translation initiation factor involved in stem cell fate shapes the synthesis of specific signalling factors.
Cost-effectiveness of a domestic violence and abuse training and support programme in primary care in the real world: updated modelling based on an MRC phase IV observational pragmatic implementation
Publisher: BMJ
Date: 08-2018
DOI: 10.1136/BMJOPEN-2017-021256
Abstract: To evaluate the cost-effectiveness of the implementation of the Identification and Referral to Improve Safety (IRIS) programme using up-to-date real-world information on costs and effectiveness from routine clinical practice. A Markov model was constructed to estimate mean costs and quality-adjusted life-years (QALYs) of IRIS versus usual care per woman registered at a general practice from a societal and health service perspective with a 10-year time horizon. Cost–utility analysis in UK general practices, including data from six sites which have been running IRIS for at least 2 years across England. Based on the Markov model, which uses health states to represent possible outcomes of the intervention, we stipulated a hypothetical cohort of 10 000 women aged 16 years or older. The IRIS trial was a randomised controlled trial that tested the effectiveness of a primary care training and support intervention to improve the response to women experiencing domestic violence and abuse, and found it to be cost-effective. As a result, the IRIS programme has been implemented across the UK, generating data on costs and effectiveness outside a trial context. The IRIS programme saved £14 per woman aged 16 years or older registered in general practice (95% uncertainty interval −£151 to £37) and produced QALY gains of 0.001 per woman (95% uncertainty interval −0.005 to 0.006). The incremental net monetary benefit was positive both from a societal and National Health Service perspective (£42 and £22, respectively) and the IRIS programme was cost-effective in 61% of simulations using real-life data when the cost-effectiveness threshold was £20 000 per QALY gained as advised by National Institute for Health and Care Excellence. The IRIS programme is likely to be cost-effective and cost-saving from a societal perspective in the UK and cost-effective from a health service perspective, although there is considerable uncertainty surrounding these results, reflected in the large uncertainty intervals.
Related Organisations
City, University Of London
Location: United Kingdom of Great Britain and Northern Ireland
University Of Bristol
Location: United Kingdom of Great Britain and Northern Ireland
University Of York
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
No related grants have been discovered for Ramona Weber.