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RNA G-quadruplexes at upstream open reading frames cause DHX36- and DHX9-dependent translation of human mRNAs.

Published version
Peer-reviewed

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Authors

Murat, Pierre 
Marsico, Giovanni 
Herdy, Barbara 
Ghanbarian, Avazeh T 
Portella, Guillem 

Abstract

BACKGROUND: RNA secondary structures in the 5'-untranslated regions (5'-UTR) of mRNAs are key to the post-transcriptional regulation of gene expression. While it is evident that non-canonical Hoogsteen-paired G-quadruplex (rG4) structures somehow contribute to the regulation of translation initiation, the nature and extent of human mRNAs that are regulated by rG4s is not known. Here, we provide new insights into a mechanism by which rG4 formation modulates translation. RESULTS: Using transcriptome-wide ribosome profiling, we identify rG4-driven mRNAs in HeLa cells and reveal that rG4s in the 5'-UTRs of inefficiently translated mRNAs associate with high ribosome density and the translation of repressive upstream open reading frames (uORF). We demonstrate that depletion of the rG4-unwinding helicases DHX36 and DHX9 promotes translation of rG4-associated uORFs while reducing the translation of coding regions for transcripts that comprise proto-oncogenes, transcription factors and epigenetic regulators. Transcriptome-wide identification of DHX9 binding sites shows that reduced translation is mediated through direct physical interaction between the helicase and its rG4 substrate. CONCLUSION: This study identifies human mRNAs whose translation efficiency is modulated by the DHX36- and DHX9-dependent folding/unfolding of rG4s within their 5'-UTRs. We reveal a previously unknown mechanism for translation regulation in which unresolved rG4s within 5'-UTRs promote 80S ribosome formation on upstream start codons, causing inhibition of translation of the downstream main open reading frames. Our findings suggest that the interaction of helicases with rG4s could be targeted for future therapeutic intervention.

Description

Keywords

G-quadruplexes, Helicases, RNA secondary structures, Translation regulation, Upstream open reading frames, 5' Untranslated Regions, DEAD-box RNA Helicases, G-Quadruplexes, Humans, Neoplasm Proteins, Open Reading Frames, Polyribosomes, Protein Biosynthesis, RNA, Messenger, Transcriptome

Journal Title

Genome Biol

Conference Name

Journal ISSN

1474-7596
1474-760X

Volume Title

19

Publisher

Springer Science and Business Media LLC
Sponsorship
European Research Council (339778)
Wellcome Trust (099232/Z/12/Z)
Cancer Research UK (18618)
ERC