Fig. 4

Biogenesis and regulation of circRNAs in colorectal cancer. a | During backsplicing (left panel), base pairing between inverted repeat elements (such as Alu elements) or the dimerization of trans-acting RNA binding proteins (RBPs) brings a downstream splice-donor site (SD) into close proximity with an upstream splice-acceptor site (SA). Then, an upstream branch point (BP) attacks a downstream SD site, which subsequently attacks an upstream SA site to result in the formation of exonic circRNAs (EcircRNAs) or exon-intron circRNAs (EIcircRNAs). CircRNAs are also generated from a lariat created by an exon-skipping event during linear splicing (middle) or an intronic lariat that escapes from the debranching step of canonical linear splicing (right panel). BSJ = backsplice junction, CiRNA = circular intronic RNA. b | RBPs (e.g., QKI, ESRP1 and FUS) promote the production of circRNAs by binding the flanked intron regions of circRNAs. c | Transcription factors (e.g., ZEB1, c-Myb and c-Jun) have been shown to increase circRNA expression by physically binding the promoter region of circRNAs. d | PI3KK-mediated DHX9 phosphorylation may impair the capacity of DHX9 to resolve RNA pairing, inducing the expression of circCCDC66. e | The base pairing between reverse complementary sequences (RCMs), particularly Alu elements located in the upstream and downstream introns, bring flanking introns in close proximity to promote backsplicing. f | Certain drugs, chemokines and stress induce or inhibit the expression of circRNAs through unknown mechanisms