Fig. 1

Biogenesis of circRNAs. A Lariat-Driven Circularization model and Intron-Driven Circularization model. The former produces a lariat because of exon skipping. The lariat makes the splicing sites of circularized exons closer than before. Then, the lariat is cut again by the exons; in this way, a circRNA and a free lariat composed of introns are produced. The latter reveals that repetitive and reverse complementary sequences in flanking introns form a stem-loop structure, which brings the splicing sites into spatial proximity. Based on composition, circRNAs are divided into 4 types including (a) CiRNAs formed by introns merely, (b) EIciRNAs with both exons and introns inside the circular structure and (c) EcircRNAs with only exons to circularize. In addition, assume that one splicing site is stationary then alternative back splicing can produce two different circRNAs, as shown in dotted lines. Products of ① corresponds to the left one in (c) and ② corresponds to the right one. B Hammerhead ribozymes (HHRs) are embedded in direct long terminal repeats (LTRs) of DNA. After transcribed into RNA, HHR catalyzes the formation of 5’OH and 2,3′ cycPh. Then RNA ligase works to form the circular structure of linear RNA