Article

5′-UTR RNA G-quadruplexes: Translation regulation and targeting

Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Nucleic Acids Research (Impact Factor: 9.11). 02/2012; 40(11):4727-41. DOI: 10.1093/nar/gks068
Source: PubMed

ABSTRACT

RNA structures in the untranslated regions (UTRs) of mRNAs influence post-transcriptional regulation of gene expression. Much
of the knowledge in this area depends on canonical double-stranded RNA elements. There has been considerable recent advancement
of our understanding of guanine(G)-rich nucleic acids sequences that form four-stranded structures, called G-quadruplexes.
While much of the research has been focused on DNA G-quadruplexes, there has recently been a rapid emergence of interest in
RNA G-quadruplexes, particularly in the 5′-UTRs of mRNAs. Collectively, these studies suggest that RNA G-quadruplexes exist
in the 5′-UTRs of many genes, including genes of clinical interest, and that such structural elements can influence translation.
This review features the progresses in the study of 5′-UTR RNA G-quadruplex-mediated translational control. It covers computational
analysis, cell-free, cell-based and chemical biology studies that have sought to elucidate the roles of RNA G-quadruplexes
in both cap-dependent and -independent regulation of mRNA translation. We also discuss protein trans-acting factors that have been implicated and the evidence that such RNA motifs have potential as small molecule target. Finally,
we close the review with a perspective on the future challenges in the field of 5′-UTR RNA G-quadruplex-mediated translation
regulation.

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Available from: Anthony Bugaut, Oct 16, 2014
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    • "It is known that guanine-and cytosine-rich regions of DNA are able to form a non-canonical nucleic acid substructure conformations comprising four-stranded DNA secondary structures, namely the G-quadruplex and i-motif. These structures are involved in the control of gene expression through regulation of transcription activity[65,66]or post-transcriptional regulation[67]. Hence, it can be hypothesised that the C-rich region of the VRN-box regulates Vrn1 transcription through formation of quadruplex structures which are destabilized by a " T-> C " transition (for variants of Vrn-A1b) or cannot be formed due to almost full deletion of the nucleotide sequence (for Vrn-A m 1a) accompanying transcription activation of VRN1. For example, mutational destabilization of the C-MYC (human oncogene) promoter G-quadruplex leads to greater transcriptional activity due to the destabilization of a DNA-protein complex, where the protein is a transcriptional repressor[68]. "
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    • "Taken together, these results suggest that hnRNP-Q1 is a novel GQ binding protein and point to a potential mechanism for hnRNP-Q1-mediated translational regulation. GQs proximal to the 5' cap have previously been shown to inhibit translation by blocking ribosome assembly or scanning (Bugaut and Balasubramanian, 2012). Therefore, hnRNP-Q1 may bind to the 5'GQ of Gap-43 mRNA and prevent ribosome assembly or scanning. "
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    • "Recently, RNA G-quadruplexes have been identified, and increasing studies indicate that these RNA G-quadruplexes play important roles in RNA biology, such as pre-mRNA splicing, RNA turnover, and mRNA targeting and translation. RNA G-quadruplexes are mainly located in the 5 0 and 3 0 UTRs of mRNA (Bugaut and Balasubramanian, 2012; Jodoin et al., 2014; Millevoi et al., 2012). Interestingly, RNA G-quadruplexes in the 5 0 UTRs may regulate mRNA translation. "
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