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

Autor: Wilczynska A; Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK. a.wilczynska@beatson.gla.ac.uk.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. a.wilczynska@beatson.gla.ac.uk., Gillen SL; Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK.; MRC Toxicology Unit, Lancaster Road, Leicester, LE1 9HN, UK., Schmidt T; Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK., Meijer HA; MRC Toxicology Unit, Lancaster Road, Leicester, LE1 9HN, UK.; Present Address: Division of Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK., Jukes-Jones R; MRC Toxicology Unit, Lancaster Road, Leicester, LE1 9HN, UK., Langlais C; MRC Toxicology Unit, Lancaster Road, Leicester, LE1 9HN, UK., Kopra K; MRC Toxicology Unit, Lancaster Road, Leicester, LE1 9HN, UK.; Present Address: Department of Chemistry, University of Turku, Vatselankatu 2, FI-20500, Turku, Finland., Lu WT; MRC Toxicology Unit, Lancaster Road, Leicester, LE1 9HN, UK., Godfrey JD; MRC Toxicology Unit, Lancaster Road, Leicester, LE1 9HN, UK., Hawley BR; MRC Toxicology Unit, Lancaster Road, Leicester, LE1 9HN, UK., Hodge K; Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK., Zanivan S; Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Cain K; MRC Toxicology Unit, Lancaster Road, Leicester, LE1 9HN, UK., Le Quesne J; MRC Toxicology Unit, Lancaster Road, Leicester, LE1 9HN, UK., Bushell M; Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK. m.bushell@beatson.gla.ac.uk.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. m.bushell@beatson.gla.ac.uk.
Jazyk: angličtina
Zdroj: Genome biology [Genome Biol] 2019 Dec 02; Vol. 20 (1), pp. 262. Date of Electronic Publication: 2019 Dec 02.
DOI: 10.1186/s13059-019-1857-2
Abstrakt: 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.
Databáze: MEDLINE
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