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


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

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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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    ABSTRACT: Background: In wheat, the vernalization requirement is mainly controlled by the VRN genes. Different species of hexaploid and tetraploid wheat are widely used as genetic source for new mutant variants and alleles for fundamental investigations and practical breeding programs. In this study, VRN-A1 and VRN-B1 were analysed for 178 accessions representing six tetraploid wheat species (Triticum dicoccoides, T. dicoccum, T. turgidum, T. polonicum, T. carthlicum, T. durum) and five hexaploid species (T. compactum, T. sphaerococcum, T. spelta, T. macha, T. vavilovii). Results: Novel allelic variants in the promoter region of VRN-A1 and VRN-B1 were identified based on the change in curvature and flexibility of the DNA molecules. The new variants of VRN-A1 (designated as Vrn-A1a.2, Vrn-A1b.2 - Vrn-A1b.6 and Vrn-A1i) were found to be widely distributed in hexaploid and tetraploid wheat, and in fact were predominant over the known VRN-A1 alleles. The greatest diversity of the new variants of VRN-B1 (designated as VRN-B1.f, VRN-B1.s and VRN-B1.m) was found in the tetraploid and some hexaploid wheat species. Conclusions: New allelic variants of the VRN-A1 and VRN-B1 genes were identified in hexaploid and tetraploid wheat. Mutations in A-tract and C-rich segments within the VRN-box of VRN-A1 are associated with modulation of the vernalization requirement and flowering time. New allelic variants will be useful in fundamental investigations into the regulation of VRN1 expression, and provide a valuable genetic resource for practical breeding of wheat.
    Full-text · Article · Jan 2016 · BMC Plant Biology
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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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    ABSTRACT: Post-transcriptional regulation of gene expression by mRNA binding proteins is critical for neuronal development and function. hnRNP-Q1 is an mRNA binding protein that regulates mRNA processing events including translational repression. hnRNP-Q1 is highly expressed in brain tissue suggesting a function in regulating genes critical for neuronal development. Here we have identified Growth associated protein 43 (Gap-43) mRNA as a novel target of hnRNP-Q1 and demonstrate that hnRNP-Q1 represses Gap-43 mRNA translation and consequently GAP-43 function. GAP-43 is a neuronal protein that regulates actin dynamics in growth cones and facilitates axonal growth. Previous studies have identified factors that regulate Gap-43 mRNA stability and localization, but it remains unclear whether Gap-43 mRNA translation is also regulated. Our results reveal that hnRNP-Q1 knockdown increased nascent axon length, total neurite length and neurite number in mouse embryonic cortical neurons and enhanced Neuro2a cell process extension; these phenotypes were rescued by GAP-43 knockdown. Additionally, we have identified a G-Quadruplex structure in the 5'-UTR of Gap-43 mRNA that directly interacts with hnRNP-Q1 as a means to inhibit Gap-43 mRNA translation. Therefore, hnRNP-Q1-mediated repression of Gap-43 mRNA translation provides an additional mechanism for regulating GAP-43 expression and function and may be critical for neuronal development.
    Preview · Article · Dec 2015 · Molecular Biology of the Cell
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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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    ABSTRACT: RNA G-quadruplexes (G4s) play important roles in RNA biology. However, the function and regulation of mRNA G-quadruplexes in embryonic development remain elusive. Previously, we identified RHAU (DHX36, G4R1) as an RNA helicase that resolves mRNA G-quadruplexes. Here, we find that cardiac deletion of Rhau leads to heart defects and embryonic lethality in mice. Gene expression profiling identified Nkx2-5 mRNA as a target of RHAU that associates with its 5' and 3' UTRs and modulates its stability and translation. The 5' UTR of Nkx2-5 mRNA contains a G-quadruplex that requires RHAU for protein translation, while the 3' UTR of Nkx2-5 mRNA possesses an AU-rich element (ARE) that facilitates RHAU-mediated mRNA decay. Thus, we uncovered the mechanisms underlying Nkx2-5 post-transcriptional regulation during heart development. Meanwhile, this study demonstrates the function of mRNA 5' UTR G-quadruplex-mediated protein translation in organogenesis.
    Full-text · Article · Oct 2015 · Cell Reports
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