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 > School 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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