Figure 1.

Exon skipping and back-splicing mechanisms [7,12]. For exon skipping (green line), a lariat is created by skipping an exon during the normal splicing mechanism (attack of a 2′-OH group of defined adenosine within the intron onto the 5′-splice site at the 5′ exon (Exon 1) to generate a free 3′-OH, then the nucleophilic attack of the generated 3′-OH onto the 3′-splice). Then, lariat splicing occurs, resulting in Ecircular RNA formation. For back-splicing (purple line), intronic complementary sequences such as Alu elements (abundant transposable elements in primate genome) pair and form an RNA duplex (RNA-binding protein-driven pairing is also possible) that closely juxtapose the splice sites for nucleophilic attack of the 5′-branch point onto a 3′-splice donor and the subsequent attack of the 3′-splice donor onto a 5′-splice acceptor, resulting in the formation of exon-intron circRNA (EIcircRNA) with intron retention or exonic circRNA (EcircRNA) after internal splicing.