Pre-mRNA structures forming circular RNAs

Circular RNAs are a recently discovered class of RNAs formed by covalently linking the 5' and 3' end of an RNA. Pre-mRNAs generate circular RNAs through a back-splicing mechanism. Whereas in linear splicing a 5' splice site is connected to a downstream 3' splice site, in back-splicing the 5' splice site is connected to an upstream 3' splice site. Both mechanisms use the spliceosome for catalysis. For back-splicing to occur, the back-splice sites must frequently be brought into close proximity, which is achieved through the formation of secondary structures in the pre-mRNA. In general, these pre-mRNA structures are formed by RNA base pairing between complementary sequences flanking the back-splicing sites. Proteins can abolish these RNA structures through binding to one of the complementary strands. However, proteins can also promote back-splicing without strong RNA structures through multimerization after binding to intronic regions flanking circular exons. In humans, Alu-elements comprising around 11% of the human genome are the best-characterized elements generating structures promoting circular RNA formation. Thus, intronic pre-mRNA structures contribute to the formation of circular RNAs. •Circular RNAs are an emerging class of RNAs•The formation of circular RNAs is promoted by double stranded regions in the pre-mRNA•RNA modifying enzymes, helicases and splicing regulators impact double stranded region formation•Primate-specific Alu elements and deep intronic mutations possibly act through circular RNAs