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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    • "Next, we undertook to nail the underlying mechanism of HULC eliciting CLOCK. A previous study described that lncRNA interacted with and stabilized mRNA [28], and RNA structure in the UTRs of mRNAs influences posttranscriptional regulation of gene expression [29]. "
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    ABSTRACT: Clock circadian regulator (CLOCK)/brain and muscle arnt-like protein-1 (BMAL1) complex governs the regulation of circadian rhythm through triggering periodic alterations of gene expression. However, the underlying mechanism of circadian clock disruption in hepatocellular carcinoma (HCC) remains unclear. Here, we report that a long noncoding RNA (lncRNA), highly upregulated in liver cancer (HULC), contributes to the perturbations in circadian rhythm of hepatoma cells. Our observations showed that HULC was able to heighten the expression levels of CLOCK and its downstream circadian oscillators, such as period circadian clock 1 and cryptochrome circadian clock 1, in hepatoma cells. Strikingly, HULC altered the expression pattern and prolonged the periodic expression of CLOCK in hepatoma cells. Mechanistically, the complementary base pairing between HULC and the 5' untranslated region of CLOCK mRNA underlay the HULC-modulated expression of CLOCK, and the mutants in the complementary region failed to achieve the event. Moreover, immunohistochemistry staining and quantitative real-time polymerase chain reaction validated that the levels of CLOCK were elevated in HCC tissues, and the expression levels of HULC were positively associated with those of CLOCK in clinical HCC samples. In functional experiments, our data exhibited that CLOCK was implicated in the HULC-accelerated proliferation of hepatoma cells in vitro and in vivo. Taken together, our data show that an lncRNA, HULC, is responsible for the perturbations in circadian rhythm through upregulating circadian oscillator CLOCK in hepatoma cells, resulting in the promotion of hepatocarcinogenesis. Thus, our finding provides new insights into the mechanism by which lncRNA accelerates hepatocarcinogenesis through disturbing circadian rhythm of HCC. Copyright © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.
    Neoplasia (New York, N.Y.) 01/2015; 17(1):79-88. DOI:10.1016/j.neo.2014.11.004 · 4.25 Impact Factor
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    • "Distribution and existence of the G-quadruplex Based on G-quadruplex search algorithms, computational surveys of the human genome have revealed that putative G-quadruplex forming sequences (PQS), carrying a signature motif G !3 N x G !3 N x G !3 N x G !3 N x , are prevalent in the genome, with an estimate of ~370,000 motifs [11e14]. These PQS are frequently within human telomeric DNA, rDNA, transcription start sites [15], the promoter regions [16], and untranslated regions of mRNA [17] suggesting that G4 structures may play a pivotal role in the control of a variety of cellular processes, including telomere maintenance , ribosome biogenesis, gene replication, transcription and translation. Strikingly, these structures are often over-represented in proto-oncogenes and apparently deleted in tumor suppressor genes, which suggests evolutionary selection for G-quadruplex structures based on their function; thus, G-quadruplexes may be required to control oncogene expression [14]. "
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    ABSTRACT: G-Quadruplex nucleic acids or G-quadruplexes (G4s) are four-stranded DNA or RNA secondary structures that are formed in guanine-rich sequences. They are widely distributed in functional regions of the human genome, such as telomeres, ribosomal DNA (rDNA), transcription start sites, promoter regions and untranslated regions of mRNA, suggesting that G-quadruplex structures may play a pivotal role in the control of a variety of cellular processes. G-Quadruplexes are viewed as valid therapeutic targets in human cancer diseases. Small molecules, from naturally occurring to synthetic, are exploited to specifically target G-quadruplexes and have proven to be a new class of anticancer agents. Notably, alkaloids are an important source of G-quadruplex ligands and have significant bioactivities in anticancer therapy. In this review, the authors provide a brief, up-to-date summary of heterocyclic alkaloids and their derivatives targeting G-quadruplexes. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
    European Journal of Medicinal Chemistry 11/2014; 97(32). DOI:10.1016/j.ejmech.2014.11.021 · 3.45 Impact Factor
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    • "G-quadruplexes are increasingly recognized as elements that control translation [5], [14]. Interestingly, also transcripts for TGFβ2 and CyclinD3 contain G-quadruplex structure [1], [56]. "
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    ABSTRACT: Induction of cell proliferation requires a concomitant increase in the synthesis of glycosylated lipids and membrane proteins, which is dependent on ER-Golgi protein transport by CopII-coated vesicles. In this process, retrograde transport of ER resident proteins from the Golgi is crucial to maintain ER integrity, and allows for anterograde transport to continue. We previously showed that expression of the CopI specific SNARE protein Use1 (Unusual SNARE in the ER 1) is tightly regulated by eIF4Edependent translation initiation of Use1 mRNA. Here we investigate the mechanism that controls Use1 mRNA translation. The 5'UTR of mouse Use1 contains a 156 nt alternatively spliced intron. The non-spliced form is the predominantly translated mRNA. The alternatively spliced sequence contains G-repeats that bind the RNAbinding protein G-rich sequence binding factor 1 (Grsf1) in RNA band shift assays. The presence of these G-repeats rendered translation of reporter constructs dependent on the Grsf1 concentration. Down regulation of either Grsf1 or Use1 abrogated expansion of erythroblasts. The 5'UTR of human Use1 lacks the splice donor site, but contains an additional upstream open reading frame in close proximity of the translation start site. Similar to mouse Use1, G-repeats located in front of human Use1 start codon promote translation of human Use1. In conclusion, Grsf1 controls translation of the SNARE protein Use1, possibly by positioning the 40S ribosomal subunit and associated translation factors in front of the translation start site. Given the essential role of SNARE protein Use1 in retrograde transport, our data suggest that ER-Golgi transport may be under control of selective mRNA translation.
    PLoS ONE 08/2014; 9(9). DOI:10.1371/journal.pone.0104631 · 3.23 Impact Factor
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