eIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5’UTR

Wilczynska, A. et al. (2019) eIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5’UTR. Genome Biology, 20, 262. (doi: 10.1186/s13059-019-1857-2) (PMID:31791371) (PMCID:PMC6886185)

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Abstract

Background: Regulation of the mRNA life cycle is central to gene expression control and determination of cell fate. miRNAs represent a critical mRNA regulatory mechanism, but despite decades of research, their mode of action is still not fully understood. Results: Here, we show that eIF4A2 is a major effector of the repressive miRNA pathway functioning via the Ccr4-Not complex. We demonstrate that while DDX6 interacts with Ccr4-Not, its effects in the mechanism are not as pronounced. Through its interaction with the Ccr4-Not complex, eIF4A2 represses mRNAs at translation initiation. We show evidence that native eIF4A2 has similar RNA selectivity to chemically inhibited eIF4A1. eIF4A2 exerts its repressive effect by binding purine-rich motifs which are enriched in the 5′UTR of target mRNAs directly upstream of the AUG start codon. Conclusions: Our data support a model whereby purine motifs towards the 3′ end of the 5′UTR are associated with increased ribosome occupancy and possible uORF activation upon eIF4A2 binding.

Item Type:Articles
Additional Information:This work was supported by Cancer Research UK core grant number A17196, A29252, core funding from the Medical Research Council MC_UP_A600_1024, MRC Senior Fellowship to MB MC_EX_G0902052, BBSRC BB/N017005/1, and BBSRC BB/M001865/1.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Le Quesne, Professor John and Zanivan, Professor Sara and Wilczynska, Dr Ania and Bushell, Professor Martin
Authors: Wilczynska, A., Gillen, S. L., Schmidt, T., Meijer, H. A., Jukes-Jones, R., Langlais, C., Kopra, K., Lu, W.-T., Godfrey, J. D., Hawley, B. R., Hodge, K., Zanivan, S., Cain, K., Le Quesne, J., and Bushell, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Genome Biology
Publisher:BioMed Central
ISSN:1474-760X
ISSN (Online):1465-6906
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Genome Biology 20:262
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
307083Mechanistic determination of how microRNAs control gene-expressionMartin BushellBiotechnology and Biological Sciences Research Council (BBSRC)BB/N017005/2CS - Beatson Institute for Cancer Research