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RNA structures in alternative splicing and back‐splicing

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Abstract Alternative splicing greatly expands the transcriptomic and proteomic diversities related to physiological and developmental processes in higher eukaryotes. Splicing of long noncoding RNAs, and back‐ and trans‐ splicing further expanded the regulatory repertoire of alternative splicing. RNA structures were shown to play an important role in regulating alternative splicing and back‐splicing. Application of novel sequencing technologies made it possible to identify genome‐wide RNA structures and interaction networks, which might provide new insights into RNA splicing regulation in vitro to in vivo. The emerging transcription–folding–splicing paradigm is changing our understanding of RNA alternative splicing regulation. Here, we review the insights into the roles and mechanisms of RNA structures in alternative splicing and back‐splicing, as well as how disruption of these structures affects alternative splicing and then leads to human diseases. This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems
The regulatory role of RNA structures in the back‐splicing. (a) Back‐splicing is regulated by RNA secondary structure interaction. The RNA secondary structure formed by intron complementary pairing takes the downstream splice donor and the upstream splice acceptor close together, and induces back‐splicing event. (b) Competing RNA secondary structures mediates alternative back‐splicing. Competition of RNA secondary structures between upstream complementary repeats and inverted complementary repeats downstream of multiple exons results in the formation of different kinds of circRNAs. circRNA, circular RNA; E2, exon 2; E3, exon 3
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Dynamic RNA structures regulate alternative splicing. (a) Competing RNA secondary structure regulate alternative splicing. The variable exons are suppressed by splicing suppressors (red ovals). Competitive complementary pairing of the upstream element (called docking site in Dscam exon6) and multiple downstream elements (called selector sequences in Dscam exon6) regulates the selection of variable exons (Graveley, 2005). When the upstream element is base‐paired with the element upstream of the exon Y (blue oval), the upstream enhancer and their binding proteins are brought closer to the exon Y (blue oval) to inactivate the suppressor protein, leading to the exon inclusion (left). In contrast, when an upstream element is base‐paired with the element upstream of the exon Z (purple oval), the exon will be included (right). (b) Dynamic RBP‐RNA interaction regulates alternative splicing. Changes in RNA secondary structure cause RNA motifs to be included in the double‐stranded stem region or released into a single‐stranded or loop region, thereby leading to the switch‐off (left) or switch‐on (right) for RBP switch. (c) TPP riboswitches regulate mRNA splicing. In low TPP concentration, the TPP aptamer is complementary to the adjacent 5′ splice site (the second 5′ splice site) and thereby prevent splicing. The long intron between the first 5′ splice site and the downstream 3′ splice site is spliced, resulting in formation of short transcripts that permit high expression. In high TPP concentration, the structural conformation of the aptamer is changed by binding with TPP ligand, thereby exposing the second 5′ splice site. Splicing occurs between it and the downstream 3′ splice site and removes the shorter intron. The resulting transcripts contain an upstream ORF (uORF) that competes with the translation of the main ORF. (d) Roles of repeat‐associated RNA structure in the alternative splicing. Muscleblind‐like (MBNL) sequestration by the expanded microsatellite repeat leads to aberrant splicing in DM1. CTG trinucleotide repeats ([CTG]n) are present in the 3′ UTR region of the dystrophia myotonia protein kinase (DMPK) gene. Under normal circumstances, normal CUG repeats have no significant effect on MBNL1 (blue ovals) concentration, and high concentrations of MBNL1 as splicing regulatory proteins are involved in correct splicing of targeted pre‐mRNA (upper). In DM1, the expansion of CUG repeats recruits and sequesters MBNL1, and significantly reducing free, functional MBNL1 concentrations, and leading to various aberrant splicing events directly related to disease symptoms (lower). (e) G‐quadruplex structures bind RBP to regulate pre‐mRNA splicing. G tracts are abundant downstream of variable exon (e.g., CD44; yellow), which can form G‐quadruplex and serve as a binding site for heterogeneous nuclear ribonucleoprotein F (hnRNPF) and promote inclusion of alternative exon
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The diverse mechanisms of RNA structures in alternative splicing. (a) RNA structures repress the exon within the loop. (b) RNA structures inhibit splicing via masking branchpoint or splice site. (c) Splice site is altered by RNA structure‐mediated RNA editing. (d) m6A alters the RNA structure, resulting in the exposure of protein binding sites. (e) Cis‐acting regulatory elements are occluded or exposed by RNA structure. (f) RNA structures act as a target for splicing regulatory proteins to mediate the alternative splicing. (g) RNA secondary structures bring the 5′ and 3′ splice sites or intervening elements into proximity for splicing. DsRNA, double‐stranded RNA; RBP, RNA binding protein
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A framework for evolution‐guided discovery of RNA secondary structures. (a) A general framework for RNA secondary structure prediction. First, a set of orthologous sequences across a phylogeny of species are aligned to obtain conserved regions (green background). Then, the conserved region is folded to predict the possible RNA secondary structure (marked by hearts and saddle shapes). (b) Multiple clades of sequences are used to improve the accuracy and coverage of RNA secondary structure prediction. In most cases, sequences can be predicted to form conservative secondary structures in a different clade of species, although the paired primary sequences are scattered. In most cases, sequences can predict conservative secondary structure in a different clade of species, although the paired primary sequences are divergent. Therefore, examining RNA secondary structures will show the big advantage based on multiple clades of sequence rather than examining the certain small clade
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Extended knowledge on alternative splicing. (a) Long noncoding RNA (lncRNA) produces different types of RNA through alternative 5′ splice sites and intron retention. (b) Selection of alternative 5′ splice sites allows back‐splicing of the pre‐mRNA to produce different types of circular RNA (circRNA). (c) Two identical (or different) precursor transcripts produce multiple chimeric mRNAs by alternative trans‐splicing
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RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems
RNA Processing > Splicing Regulation/Alternative Splicing

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