Circular RNAs: Biogenesis, Function, and a Role as Possible Cancer Biomarkers

Figure 1

Schematic representation of circRNA biogenesis. (a) Canonical pre-mRNA splicing, yielding a mature mRNA molecule. (b) Lariat-driven circularization (exon skipping). Following canonical splicing, exons in exon-containing lariats undergo back-splicing and circularization, which results in the formation of ecircRNA or EIciRNA molecules. (c) Intron pairing-driven circularization, utilizing coupling of flanking introns by direct base pairing between cis-acting regulatory elements that contain reverse complementary sequences (e.g., Alu repeats). Intron pairing is followed by back-splicing and exon circularization. (d) CircRNA biogenesis, mediated by trans-acting factors, such as RNA-binding proteins (RBPs) (e.g., QKI, MBL/MBNL1) that bind to specific sequence motifs of flanking introns on linear pre-mRNA, dimerize, and facilitate back-splicing and exon circularization. (e) Regulation of circRNA biogenesis by the RNA-editing enzyme ADAR. ADAR destabilizes intron base pairing interactions through the action of adenosine-to-inosine (A-to-I) editing, which impairs pre-mRNA looping and diminishes exon circularization. (f) Resplicing-driven circularization. EcircRNAs may be formed from mature mRNA exons that undergo back-splicing and circularization. (g) Formation of ciRNAs from intron lariats that escape the usual intron debranching and degradation, following the canonical pre-mRNA splicing. (h) Formation of intergenic circRNAs. This figure is adapted from Wang et al. [151].