Circular RNAs (circRNAs) are covalently closed RNA molecules without 5' to 3' polarity or poly(A) tail. Unlike linear RNAs, circRNAs were previously under-estimated in polyadenylated transcriptome analyses. Recent advances in biochemical and computational methods have identified numerous circRNAs from back-spliced exons in various species. Back-splicing, which requires canonical spliceosomal machinery and can be facilitated by complementary sequences and protein factors, is a key mechanism for circRNA biogenesis. CircRNAs are often generated through competition between back-splicing and canonical splicing, with back-splicing leading to covalently closed circRNAs and canonical splicing producing linear RNAs with skipped exons.
The biogenesis of circRNAs via back-splicing differs from canonical splicing and other forms of circular RNA formation. Two models explain circRNA formation: the "exon skipping" model, where canonical splicing precedes back-splicing, and the "direct back-splicing" model, where back-splicing occurs first. Both models involve competition between back-splicing and canonical splicing, with cis-elements and trans-factors regulating this process. RNA pairing across flanking introns or within a single intron can promote either back-splicing or canonical splicing, leading to the production of circRNAs or linear RNAs.
Several RNA-binding proteins, such as MBNL1 and ADAR1, play roles in circRNA biogenesis. MBNL1 promotes back-splicing by bridging flanking introns, while ADAR1 suppresses circRNA biogenesis through A-to-I RNA editing. The regulation of circRNA biogenesis is complex, involving multiple cis- and trans-factors. Alternative circularization, where multiple circRNAs are generated from a single gene locus, is a significant phenomenon, influenced by RNA pairing and intron retention.
CircRNAs are not merely by-products of splicing errors but are regulated circular RNAs with distinct cis- and trans-factors. Some circRNAs are more abundant than their linear counterparts and may function as long non-coding RNAs (lncRNAs). Exogenous circRNAs with internal ribosome entry sites (IRES) can be translated in vitro or in vivo. The function of circRNAs remains an area of active research, with some circRNAs implicated in gene regulation, RNA Pol II transcription, and acting as miRNA sponges. Future studies aim to elucidate the roles of circRNAs in physiological and pathological conditions.Circular RNAs (circRNAs) are covalently closed RNA molecules without 5' to 3' polarity or poly(A) tail. Unlike linear RNAs, circRNAs were previously under-estimated in polyadenylated transcriptome analyses. Recent advances in biochemical and computational methods have identified numerous circRNAs from back-spliced exons in various species. Back-splicing, which requires canonical spliceosomal machinery and can be facilitated by complementary sequences and protein factors, is a key mechanism for circRNA biogenesis. CircRNAs are often generated through competition between back-splicing and canonical splicing, with back-splicing leading to covalently closed circRNAs and canonical splicing producing linear RNAs with skipped exons.
The biogenesis of circRNAs via back-splicing differs from canonical splicing and other forms of circular RNA formation. Two models explain circRNA formation: the "exon skipping" model, where canonical splicing precedes back-splicing, and the "direct back-splicing" model, where back-splicing occurs first. Both models involve competition between back-splicing and canonical splicing, with cis-elements and trans-factors regulating this process. RNA pairing across flanking introns or within a single intron can promote either back-splicing or canonical splicing, leading to the production of circRNAs or linear RNAs.
Several RNA-binding proteins, such as MBNL1 and ADAR1, play roles in circRNA biogenesis. MBNL1 promotes back-splicing by bridging flanking introns, while ADAR1 suppresses circRNA biogenesis through A-to-I RNA editing. The regulation of circRNA biogenesis is complex, involving multiple cis- and trans-factors. Alternative circularization, where multiple circRNAs are generated from a single gene locus, is a significant phenomenon, influenced by RNA pairing and intron retention.
CircRNAs are not merely by-products of splicing errors but are regulated circular RNAs with distinct cis- and trans-factors. Some circRNAs are more abundant than their linear counterparts and may function as long non-coding RNAs (lncRNAs). Exogenous circRNAs with internal ribosome entry sites (IRES) can be translated in vitro or in vivo. The function of circRNAs remains an area of active research, with some circRNAs implicated in gene regulation, RNA Pol II transcription, and acting as miRNA sponges. Future studies aim to elucidate the roles of circRNAs in physiological and pathological conditions.