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

Wilczynska, Ania, Gillen, Sarah L., Schmidt, Tobias, Meijer, Hedda A., Jukes-Jones, Rebekah, Langlais, Claudia, Kopra, Kari, Lu, Wei-Ting, Godfrey, Jack D., Hawley, Benjamin R., Hodge, Kelly, Zanivan, Sara, Cain, Kelvin, Le Quesne, John, Bushell, Martin·2019·Genome Biology
DOI 10.1186/s13059-019-1857-2PMC 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.

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Metadata

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., & Bushell, M.
Venue
Genome Biology
Publisher
Springer Science and Business Media LLC
Published
2019-12
Volume
20
Issue
1
ISSN
1474-760X
DOI
10.1186/s13059-019-1857-2
PMC
PMC6886185
Cited by
62
References
8
Language
en
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