Figure 2.

Proteins involved in circRNA biogenesis and potential mechanism of their actions. Exons are represented by rectangles, as in Figure 1, the “T” bars indicate inhibition of circRNA formation. (A) Mbl/MBNLs, Quaking (QKI) and Fused in Sarcoma (FUS) proteins can promote circRNAs biogenesis via binding in their RNA-binding motifs in introns adjacent to the back-splicing junctions facilitating the bridging process. (B) hnRNPs (heterogeneous nuclear ribonucleoproteins) and SR (serine-arginine) proteins can act in a combinatorial manner to either stimulate or inhibit circRNAs formation. Depletion of SR proteins (SRSF1, SRSF11 and SRSF6) each can cause an increase of circRNAs level. Similarly, hnRNP protein Hrb27C acts to impede circRNAs generation, whereas Hrb87F can enhance the process. In addition, simultaneous depletion of Hrb27C with SRSF1, SRSF11 and SRSF6 cause an additive effect and increase of circRNAs expression, suggesting that each of these factors plays a non-redundant role. (C) ADAR1 protein hampers circRNAs biogenesis via destabilizing double-stranded RNA interactions of introns flanking circRNA-forming exons through site-specific deamination of adenosine bases to inosines. ADAR1 interferes with RNA-RNA interactions between inverted repeats present in circRNA-flanking introns (shown as pink arrows) and prevents the formation of structures promoting circularization of exons.