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The role of RNA G‐quadruplexes in human diseases and therapeutic strategies

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Abstract G‐quadruplexes (GQs) are four‐stranded secondary structures formed by G‐rich nucleic acid sequence(s). DNA GQs are present abundantly in the genome and affect a wide range of processes associated with DNA. Recent studies show that RNA GQs are present in different transcripts, including coding and noncoding areas of mRNA, telomeric RNA as well as in other premature and mature noncoding RNAs. When present at specific locations within the RNAs, GQs play important roles in key biological functions, including the regulation of gene expression and telomere homeostasis. RNA GQs regulate pre‐mRNA processing, such as splicing and polyadenylation. Evidently, among other processes, RNA GQs also control mRNA translation, miRNA and piRNA biogenesis, and RNA localization. The regulatory mechanisms controlled by RNA GQs mainly involve binding to RNA binding protein that modulate GQ conformation or serve as an entity in recruiting additional protein regulators to act as a block element to the processing machinery. Here we provide an overview of the ever‐increasing number of discoveries revealing the role of RNA GQs in biology and their relevance in human diseases and therapeutics. This article is categorized under: RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems RNA in Disease and Development > RNA in Disease
G‐quadruplex (GQ) in RNA biology: (a) a square planar G‐quartet assembly is formed via Hoogsteen hydrogen bonding between four guanine bases; (b) G‐quartets can stack on top of each other to form the GQ structure, which is stabilized by monovalent cation(s); (c) RNA GQs impact in RNA biology either via RBP interaction or by blocking the RNA processes and (d) RNA GQs are implicated in diseases including cancers, neurological disorders, and viral pathogenesis
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Strategies for targeting RNA G‐quadruplexes (GQs) using nucleic acid‐based therapeutic molecules. (a) Some of the commonly used GQ targeting small molecules; (b) a lock‐nucleic acid (LNA) molecule sequence targets the sequence downstream of a GQ, prohibiting the formation of canonical stem‐loop structure in miRNA 92b hence inhibiting the miRNA 92b maturation and a PEGylated nucleic acid clamp therapeutic can be used to target the flanking ends of a GQ, creating a more stable structure in order to modulate the downstream processes
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RNA G‐quadruplexes interfere with the biogenesis and function of both miRNA (left) and piRNA (right)
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RNA G‐quadruplexes (GQs) in ncRNA biology. ncRNA GQs have been implicated in the biogenesis and maturation of small ncRNAs, telomere homeostasis, and in the function of rRNA and lncRNA
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RNA G‐quadruplexes (GQs) in mRNA biology. mRNA GQs have been implicated in mRNA biogenesis, stability, translation, and translocation
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RNA in Disease and Development > RNA in Disease
RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems

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