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

Ania Wilczynska (Lead / Corresponding author), Sarah L. Gillen, Tobias Schmidt, Hedda A. Meijer, Rebekah Jukes-Jones, Claudia Langlais, Kari Kopra, Wei-Ting Lu, Jack D. Godfrey, Benjamin R. Hawley, Kelly Hodge, Sara Zanivan, Kelvin Cain, John Le Quesne, Martin Bushell

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)
32 Downloads (Pure)

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.

Original languageEnglish
Article number262
Pages (from-to)1-21
Number of pages21
JournalGenome Biology
Volume20
DOIs
Publication statusPublished - 2 Dec 2019

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