eIF4A2 drives repression of translation at initiation by Ccr4-Not through purine-rich motifs in the 5′UTR
: 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 Bushell
Publisher: BMC
: 2019
: Genome Biology
: Genome Biol.
: 20
: 1
: 262
: 21
: 1474-760X
: 1474-760X
DOI: https://doi.org/10.1186/s13059-019-1857-2
: https://research.utu.fi/converis/portal/detail/Publication/44080981
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.
ResultsHere, 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.
ConclusionsOur 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.