Figure 1. CircRNA diversity and biogenesis.

(A) Pre-mRNA can be processed through either canonical splicing to produce linear RNAs or back-splicing to generate circRNAs. CircRNAs are mainly divided into three categories based on their components: exonic circRNAs (EcircRNAs) are exclusively composed of exons and represent the largest group of circRNAs, intronic circRNAs (ciRNAs) are exclusively composed of introns, and exon-intron circRNAs (EIcircRNAs) are composed of exon-intron sequences. (B) A single gene locus can produce both linear and circular transcripts by canonical splicing or back-splicing mechanisms, respectively. (C) A single gene locus can produce multiple circRNAs that share the same back-splice site through a mechanism called alternative back-splicing (ABS), due to the competition among inverted complementary sequences across introns that bracket the circRNA-forming exons. There are two types of ABS events, alternative 5′ back-splicing (A5BS) and alternative 3′ back-splicing (A3BS). In an A5BS event, two or more downstream 5′ back-splice sites are alternatively joined with the same upstream 3′ back-splice site, while for A3BS circRNAs, the same downstream 5′ back-splice site is alternatively joined with two or more upstream 3′ back-splice sites. (D) Two main models have been proposed for circular RNA formation. Model 1: Lariat-driven circularization (exon skipping). Splice donor in the 3′ end of exon 2 covalently splices to the splice acceptor in the 5′ end of exon 3 and forms a lariat via exon skipping. Model 2: Intron-pairing-driven circularization. Intron 2 and intron 4 form a circular structure via base-pairing (-) or trans factors such as RNA-binding proteins (RBPs). The introns are then removed and EIcircRNA, EcircRNA, and intron lariat (ciRNA) are formed.