s13059-019-1857-2.pdf (3.24 MB)
eIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5 ' UTR
journal contribution
posted on 2020-05-14, 14:21 authored by Ania Wilczynska, 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 BushellBackground: 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.
Funding
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. We would like to thank the Core Services and Advanced Technologies at the Cancer Research UK Beatson Institute (C596/A17196), with particular thanks to the Proteomics team.
History
Citation
Genome Biology 20, 262 (2019)Author affiliation
MRC Toxicology UnitVersion
- VoR (Version of Record)
Published in
Genome BiologyVolume
20Issue
1Publisher
BMCissn
1474-760Xeissn
1465-6906Acceptance date
2019-09-10Copyright date
2019Publisher DOI
Publisher version
https://genomebiology.biomedcentral.com/articles/10.1186/s13059-019-1857-2#Abs1Language
EnglishUsage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC