The high kinetic stability of a G-quadruplex limits hnRNP F qRRM3 binding to G-tract RNA

Samatanga, Brighton; Dominguez, Cyril; Jelesarov, Ilian; Allain, Frédéric H.‐T.

doi:10.1093/nar/gks1289

Cited by 51 publications

(47 citation statements)

References 50 publications

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“…An extensive search of the literature did not reveal any evidence about direct protein-protein interactions between FMRP and any of the splicing factors identified by the SFmap software (Supplemental Table 1), suggesting that FMRP might function to control the accessibility of the splicing factors to their RNA binding sites. Supporting this hypothesis are the findings that the binding of hnRNP F to its G-rich RNA binding site is limited by the stability of a G-quadruplex structure adopted by this sequence (Samatanga et al 2012). Specifically, it has been shown that hnRNP F does not bind to the G-quadruplex structure formed by its G-rich binding site, and there is a competition between the formation of the G-quadruplex structure and of the hnRNP F protein-RNA complex.…”

Section: Fbssh Rna Interactions With Different Fmrp Isoformsmentioning

confidence: 99%

Biophysical characterization of G-quadruplex forming FMR1 mRNA and of its interactions with different fragile X mental retardation protein isoforms

Blice-Baum

Mihailescu

2013

RNA

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Fragile X syndrome, the most common form of inherited mental impairment in humans, is caused by the absence of the fragile X mental retardation protein (FMRP) due to a CGG trinucleotide repeat expansion in the 5 ′ -untranslated region (UTR) and subsequent translational silencing of the fragile x mental retardation-1 (FMR1) gene. FMRP, which is proposed to be involved in the translational regulation of specific neuronal messenger RNA (mRNA) targets, contains an arginine-glycine-glycine (RGG) box RNA binding domain that has been shown to bind with high affinity to G-quadruplex forming mRNA structures. FMRP undergoes alternative splicing, and the binding of FMRP to a proposed G-quadruplex structure in the coding region of its mRNA (named FBS) has been proposed to affect the mRNA splicing events at exon 15. In this study, we used biophysical methods to directly demonstrate the folding of FMR1 FBS into a secondary structure that contains two specific G-quadruplexes and analyze its interactions with several FMRP isoforms. Our results show that minor splice isoforms, ISO2 and ISO3, created by the usage of the second and third acceptor sites at exon 15, bind with higher affinity to FBS than FMRP ISO1, which is created by the usage of the first acceptor site. FMRP ISO2 and ISO3 cannot undergo phosphorylation, an FMRP posttranslational modification shown to modulate the protein translation regulation. Thus, their expression has to be tightly regulated, and this might be accomplished by a feedback mechanism involving the FMRP interactions with the G-quadruplex structures formed within FMR1 mRNA.

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Section: Fbssh Rna Interactions With Different Fmrp Isoformsmentioning

confidence: 99%

Biophysical characterization of G-quadruplex forming FMR1 mRNA and of its interactions with different fragile X mental retardation protein isoforms

Blice-Baum

Mihailescu

2013

RNA

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“…In addition, two mutants with an intact G-tract but predicted to disrupt TCEI stem base pairing, TCE UAC and TCE GAC , retained both higher and lower affinity binding components (Figure S1C, D), indicating that the G-tract sequence is responsible for the higher affinity binding. These data also indicate that Glo can interact with the G-tract regardless of whether it is base-paired and suggest that, like hnRNP F (Dominguez et al 2010; Samatanga et al, 2013), Glo binding may promote a single-stranded configuration of G-tracts.…”

Section: Resultsmentioning

confidence: 69%

“…Recognition of the G-tract is instead mediated by residues located in three loops (Dominguez and Allain, 2006; Dominguez et al, 2010; Honore et al, 1995). The loop residues encage the G-tract, sequestering it in a single-stranded conformation (Dominguez et al, 2010; Samatanga et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

The Drosophila hnRNP F/H Homolog Glorund Uses Two Distinct RNA-Binding Modes to Diversify Target Recognition

Tamayo¹,

Teramoto²,

Chatterjee³

et al. 2017

Cell Reports

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Summary The Drosophila hnRNP F/H homolog, Glorund (Glo), regulates nanos mRNA translation by interacting with a structured UA-rich motif in the nanos 3′ untranslated region. Glo regulates additional RNAs however, and mammalian homologs bind G-tract sequences to regulate alternative splicing, suggesting that Glo also recognizes G-tract RNA. To gain insight into how Glo recognizes both structured UA-rich and G-tract RNAs, we used mutational analysis guided by crystal structures of Glo’s RNA-binding domains and identified two discrete RNA-binding surfaces that allow Glo to recognize both RNA motifs. By engineering Glo variants that favor a single RNA-binding mode, we show that a subset of Glo’s functions in vivo is mediated solely by the G-tract binding mode, whereas regulation of nanos requires both recognition modes. Our findings suggest a molecular mechanism for the evolution of dual RNA motif recognition in Glo that may be applied to understanding the functional diversity of other RNA-binding proteins.

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“…In mitochondria, the G-quadruplex structure in RNA facilitates the termination of DNA transcription (42). The RNA G-quadruplex affects alternative splicing, ribosomal frameshifts, and stop codon readthrough (43)(44)(45)(46). In the 3= UTR of mRNAs, the G-quadruplex structure drives subcellular relocalization and increases the efficiency of alternative polyadenylation and therefore the expression of shortened transcripts (47,48).…”

Section: Discussionmentioning

confidence: 99%

G-Quadruplex in the NRF2 mRNA 5′ Untranslated Region Regulates De Novo NRF2 Protein Translation under Oxidative Stress

Lee

Zhang

Strom

et al. 2017

Molecular and Cellular Biology

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Inhibition of protein synthesis serves as a general measure of cellular consequences of chemical stress. A few proteins are translated selectively and influence cell fate. How these proteins can bypass the general control of translation remains unknown. We found that low to mild doses of oxidants induce de novo translation of the NRF2 protein. Here we demonstrate the presence of a G-quadruplex structure in the 5= untranslated region (UTR) of NRF2 mRNA, as measured by circular dichroism, nuclear magnetic resonance, and dimethylsulfate footprinting analyses. Such a structure is important for 5=-UTR activity, since its removal by sequence mutation eliminated H 2 O 2 -induced activation of the NRF2 5= UTR. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics revealed elongation factor 1 alpha (EF1a) as a protein binding to the G-quadruplex sequence. Cells responded to H 2 O 2 treatment by increasing the EF1a protein association with NRF2 mRNA, as measured by RNA-protein interaction assays. The EF1a interaction with small and large subunits of ribosomes did not appear to change due to H 2 O 2 treatment, nor did posttranslational modifications, as measured by two-dimensional (2-D) Western blot analysis. Since NRF2 encodes a transcription factor essential for protection against tissue injury, our data have revealed a novel mechanism of cellular defense involving de novo NRF2 protein translation governed by the EF1a interaction with the G-quadruplex in the NRF2 5= UTR during oxidative stress.

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The high kinetic stability of a G-quadruplex limits hnRNP F qRRM3 binding to G-tract RNA

Cited by 51 publications

References 50 publications

Biophysical characterization of G-quadruplex forming FMR1 mRNA and of its interactions with different fragile X mental retardation protein isoforms

Biophysical characterization of G-quadruplex forming FMR1 mRNA and of its interactions with different fragile X mental retardation protein isoforms

The Drosophila hnRNP F/H Homolog Glorund Uses Two Distinct RNA-Binding Modes to Diversify Target Recognition

G-Quadruplex in the NRF2 mRNA 5′ Untranslated Region Regulates De Novo NRF2 Protein Translation under Oxidative Stress

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