RNA G-quadruplexes mark repressive upstream open reading frames in human mRNAs
bioRxiv(2017)
Abstract
RNA secondary structures in the 59 untranslated regions (UTRs) of mRNAs have been characterised as key determinants of translation initiation. However the role of non-canonical secondary structures, such as RNA G-quadruplexes (rG4s), in modulating translation of human mRNAs and the associated mechanisms remain largely unappreciated. Here we use a ribosome profiling strategy to investigate the translational landscape of human mRNAs with structured 59 untranslated regions (59-UTR). We found that inefficiently translated mRNAs, containing rG4-forming sequences in their 59-UTRs, have an accumulation of ribosome footprints in their 59-UTRs. We show that rG4-forming sequences are determinants of 59-UTR translation, suggesting that the folding of rG4 structures thwarts the translation of protein coding sequences (CDS) by stimulating the translation of repressive upstream open reading frames (uORFs). To support our model, we demonstrate that depletion of two rG4s-specialised DEAH-box helicases, DHX36 and DHX9, shifts translation towards rG4-containing uORFs reducing the translation of selected transcripts comprising proto-oncogenes, transcription factors and epigenetic regulators. Transcriptome-wide identification of DHX9 binding sites using individual-nucleotide resolution UV crosslinking and immunoprecipitation (iCLIP) demonstrate that translation regulation is mediated through direct physical interaction between the helicase and its rG4 substrate. Our findings unveil a previously unknown role for non-canonical structures in governing 59-UTR translation and suggest that the interaction of helicases with rG4s could be considered as a target for future therapeutic intervention.
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