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eIF4A1-dependent mRNAs employ purine-rich 5'UTR sequences to activate localised eIF4A1-unwinding through eIF4A1-multimerisation to facilitate translation

Schmidt, Tobias; Dabrowska, Adrianna; Waldron, Joseph A; Hodge, Kelly; Koulouras, Grigorios; Gabrielsen, Mads; Munro, June; Tack, David C; Harris, Gemma; McGhee, Ewan; Scott, David; Carlin, Leo M; Huang, Danny; Le Quesne, John; Zanivan, Sara; Wilczynska, Ania; Bushell, Martin

eIF4A1-dependent mRNAs employ purine-rich 5'UTR sequences to activate localised eIF4A1-unwinding through eIF4A1-multimerisation to facilitate translation Thumbnail


Authors

Tobias Schmidt

Adrianna Dabrowska

Joseph A Waldron

Kelly Hodge

Grigorios Koulouras

Mads Gabrielsen

June Munro

David C Tack

Gemma Harris

Ewan McGhee

DAVID SCOTT DAVID.SCOTT@NOTTINGHAM.AC.UK
Associate Professor & Reader in Physical Biochemistry

Leo M Carlin

Danny Huang

John Le Quesne

Sara Zanivan

Ania Wilczynska

Martin Bushell



Abstract

Altered eIF4A1 activity promotes translation of highly structured, eIF4A1-dependent oncogene mRNAs at root of oncogenic translational programmes. It remains unclear how these mRNAs recruit and activate eIF4A1 unwinding specifically to facilitate their preferential translation. Here, we show that single-stranded RNA sequence motifs specifically activate eIF4A1 unwinding allowing local RNA structural rearrangement and translation of eIF4A1-dependent mRNAs in cells. Our data demonstrate that eIF4A1-dependent mRNAs contain AG-rich motifs within their 5'UTR which specifically activate eIF4A1 unwinding of local RNA structure to facilitate translation. This mode of eIF4A1 regulation is used by mRNAs encoding components of mTORC-signalling and cell cycle progression, and renders these mRNAs particularly sensitive to eIF4A1-inhibition. Mechanistically, we show that binding of eIF4A1 to AG-rich sequences leads to multimerization of eIF4A1 with eIF4A1 subunits performing distinct enzymatic activities. Our structural data suggest that RNA-binding of multimeric eIF4A1 induces conformational changes in the RNA resulting in an optimal positioning of eIF4A1 proximal to the RNA duplex enabling efficient unwinding. Our data proposes a model in which AG-motifs in the 5'UTR of eIF4A1-dependent mRNAs specifically activate eIF4A1, enabling assembly of the helicase-competent multimeric eIF4A1 complex, and positioning these complexes proximal to stable localised RNA structure allowing ribosomal subunit scanning.

Journal Article Type Article
Acceptance Date Dec 22, 2022
Online Publication Date Feb 2, 2023
Publication Date Feb 28, 2023
Deposit Date Feb 3, 2023
Publicly Available Date Feb 16, 2023
Journal Nucleic Acids Research
Print ISSN 0305-1048
Electronic ISSN 1362-4962
Publisher Oxford University Press (OUP)
Peer Reviewed Peer Reviewed
Volume 51
Issue 4
Pages 1859-1879
DOI https://doi.org/10.1093/nar/gkad030
Keywords Genetics
Public URL https://nottingham-repository.worktribe.com/output/16801732
Publisher URL https://academic.oup.com/nar/article/51/4/1859/7023804

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