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      RNA G-quadruplexes and their potential regulatory roles in translation

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          ABSTRACT

          DNA guanine (G)-rich 4-stranded helical nucleic acid structures called G-quadruplexes (G4), have been extensively studied during the last decades. However, emerging evidence reveals that 5′- and 3′-untranslated regions (5′- and 3′-UTRs) as well as open reading frames (ORFs) contain putative RNA G-quadruplexes. These stable secondary structures play key roles in telomere homeostasis and RNA metabolism including pre-mRNA splicing, polyadenylation, mRNA targeting and translation. Interestingly, multiple RNA binding proteins such as nucleolin, FMRP, DHX36, and Aven were identified to bind RNA G-quadruplexes. Moreover, accumulating reports suggest that RNA G-quadruplexes regulate translation in cap-dependent and -independent manner. Herein, we discuss potential roles of RNA G-quadruplexes and associated trans-acting factors in the regulation of mRNA translation.

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          Most cited references102

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          Translational control by 5'-untranslated regions of eukaryotic mRNAs.

          The eukaryotic 5' untranslated region (UTR) is critical for ribosome recruitment to the messenger RNA (mRNA) and start codon choice and plays a major role in the control of translation efficiency and shaping the cellular proteome. The ribosomal initiation complex is assembled on the mRNA via a cap-dependent or cap-independent mechanism. We describe various mechanisms controlling ribosome scanning and initiation codon selection by 5' upstream open reading frames, translation initiation factors, and primary and secondary structures of the 5'UTR, including particular sequence motifs. We also discuss translational control via phosphorylation of eukaryotic initiation factor 2, which is implicated in learning and memory, neurodegenerative diseases, and cancer.
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            RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer

            The translational control of oncoprotein expression is implicated in many cancers. Here we report an eIF4A/DDX2 RNA helicase-dependent mechanism of translational control that contributes to oncogenesis and underlies the anticancer effects of Silvestrol and related compounds. For example, eIF4A promotes T-ALL development in vivo and is required for leukaemia maintenance. Accordingly, inhibition of eIF4A with Silvestrol has powerful therapeutic effects in vitro and in vivo. We use transcriptome-scale ribosome footprinting to identify the hallmarks of eIF4A-dependent transcripts. These include 5′UTR sequences such as the 12-mer guanine quartet (CGG)4 motif that can form RNA G-quadruplex structures. Notably, among the most eIF4A-dependent and Silvestrol-sensitive transcripts are a number of oncogenes, super-enhancer associated transcription factors, and epigenetic regulators. Hence, the 5′UTRs of selected cancer genes harbour a targetable requirement for the eIF4A RNA helicase.
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              Endonucleolytic cleavage of eukaryotic mRNAs with stalls in translation elongation.

              A fundamental aspect of the biogenesis and function of eukaryotic messenger RNA is the quality control systems that recognize and degrade non-functional mRNAs. Eukaryotic mRNAs where translation termination occurs too soon (nonsense-mediated decay) or fails to occur (non-stop decay) are rapidly degraded. We show that yeast mRNAs with stalls in translation elongation are recognized and targeted for endonucleolytic cleavage, referred to as 'no-go decay'. The cleavage triggered by no-go decay is dependent on translation and involves Dom34p and Hbs1p. Dom34p and Hbs1p are similar to the translation termination factors eRF1 and eRF3 (refs 3, 4), indicating that these proteins might function in recognizing the stalled ribosome and triggering endonucleolytic cleavage. No-go decay provides a mechanism for clearing the cell of stalled translation elongation complexes, which could occur as a result of damaged mRNAs or ribosomes, or as a mechanism of post-transcriptional control.
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                Author and article information

                Journal
                Translation (Austin)
                Translation (Austin)
                KTRS
                ktrs20
                Translation
                Taylor & Francis
                2169-074X
                2169-0731
                2016
                4 October 2016
                4 October 2016
                : 4
                : 2
                : e1244031
                Affiliations
                [a ]Terry Fox Molecular Oncology Group and Segal Cancer Center, McGill University , Montréal, Québec, Canada
                [b ]Bloomfield Center for Research on Aging, Lady Davis Institute for Medical Research, McGill University , Montréal, Québec, Canada
                [c ]Department of Oncology, McGill University , Montréal, Québec, Canada
                [d ]Department of Medicine, McGill University , Montréal, Québec, Canada
                [e ]Département de Biochimie, Université de Sherbrooke , Sherbrooke, Québec, Canada
                [f ]Department of Biochemistry, McGill University , Montréal, Québec, Canada.
                Author notes
                CONTACT Stéphane Richard stephane.richard@ 123456mcgill.ca Lady Davis Institute , 3755 Côte Ste-Catherine Road, Montréal, Québec H3T 1E2, Canada.
                Article
                1244031
                10.1080/21690731.2016.1244031
                5173311
                28090421
                6b621524-35b7-4d4a-8148-580594ed86b0
                © 2016 The Author(s). Published with license by Taylor & Francis

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.

                History
                : 16 August 2016
                : 26 September 2016
                : 28 September 2016
                Page count
                Figures: 4, Tables: 0, References: 161, Pages: 16
                Categories
                Review

                aven,dhx36,fmrp,g-quadruplexes,rna binding proteins,translation
                aven, dhx36, fmrp, g-quadruplexes, rna binding proteins, translation

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