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G‐quadruplexes in RNA biology

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Abstract G‐quadruplexes are noncanonical structures formed by G‐rich DNA and RNA sequences that fold into a four‐stranded conformation. Experimental studies and computational predictions show that RNA G‐quadruplexes are present in transcripts associated with telomeres, in noncoding sequences of primary transcripts and within mature transcripts. RNA G‐quadruplexes at these specific locations play important roles in key cellular functions, including telomere homeostasis and gene expression. Indeed, RNA G‐quadruplexes appear as important regulators of pre‐mRNA processing (splicing and polyadenylation), RNA turnover, mRNA targeting and translation. The regulatory mechanisms controlled by RNA G‐quadruplexes involve the binding of protein factors that modulate G‐quadruplex conformation and/or serve as a bridge to recruit additional protein regulators. In this review, we summarize the current knowledge on the role of G‐quadruplexes in RNA biology with particular emphasis on the molecular mechanisms underlying their specific function in RNA metabolism occurring in physiological or pathological conditions. WIREs RNA 2012, 3:495–507. doi: 10.1002/wrna.1113 This article is categorized under: RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

Guanine‐rich (G‐rich) sequence that folds into a G‐quadruplex structure, consisting of stacked coplanar arrays of four guanine bases each, called G‐quartets.

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Localization and function of G‐quadruplexes involved in mRNA translational control. G‐quadruplexes (G4) localized within the open reading frame (ORF) and both 5′ and 3′ UTRs function mainly as repressors of mRNA translation of a number of genes. G‐quadruplexes have also been found to be associated with internal ribosome entry sites (IRESs) in 5′‐UTRs and, to play a positive function in IRES‐mediated translation.

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Model of action of G‐quadruplex structures in the neuritic targeting of mRNAs. A G‐quadruplex consensus is found in many dendritically transported mRNAs, and its occurrence was demonstrated in PSD95 and CaMKIIa. The G‐quadruplex elements are often followed by an AU‐rich element, suggesting that several proteins are involved in the transport mRNP assembly. The transport into the neurites of cortical neurons is activated by metabotropic glutamate receptor (mGluR) group 1 agonists probably by recruiting additional proteins (i.e., FMRP, fragile‐X mental retardation protein and other unknown proteins) that mediate a link to KIF5 or other motor proteins for dendritic translocation.

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Localization and function of RNA G‐quadruplexes in pre‐mRNA splicing. RNA G‐quadruplexes can be associated with exon splicing enhancers (ESEs), and both intron splicing enhancers (ISEs) and silencers (ISSs). In the case of the FMR1 gene, the RNA G‐quadruplexes interact with fragile X mental retardation protein (FMRP) and FMR2 and mediates alternative splicing of FMR1 pre‐mRNA.

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Model for the role of G‐quadruplexes in regulating pre‐mRNA 3′ end processing during DNA damage. Following genotoxic insult, mRNA 3′ end formation is inhibited by a mechanism involving the sequestration of the essential polyadenylation factor CstF in a complex with BRCA1 and BARD1. A G‐quadruplex at the TP53 polyadenylation signal contributes to escape DNA damage‐induced polyadenylation inhibition through a mechanism involving the interaction between the G‐quadruplex structure and hnRNP H/F, a positive polyadenylation regulator that in turn recruits CstF and prevents it from being hijacked in alternative protein complexes. PA, polyadenylation complex.

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Regulation of telomerase activity by G‐quadruplex containing RNA molecules associated with telomeres, telomeric repeat‐containing RNA (TERRA), and TERC. TERRA RNAs fold into G‐quadruplexes, interact with both TERC and telomerase and inhibit telomerase extension. The 5′ end of the RNA moiety of the telomerase holoenzyme, TERC, is structured in a G‐quadruplex that is recognized and resolved by RNA helicase associated with AU‐rich element (RHAU), allowing the formation of the P1 helix required for template boundary definition in mammalian telomerase.

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RNA G‐quadruplexes are found in telomeric repeat‐containing RNAs (TERRAs) and TERC RNAs interacting with and regulating telomerase function and are enriched in specific locations of protein encoding transcripts where they control several gene expression steps, including pre‐mRNA splicing and polyadenylation mRNA targeting and translation.

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RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems

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