Table 1 The RNA binding proteins (RBPs) involved in the regulation of ecircRNA biogenesis
From: Circular RNAs and their roles in head and neck cancers
Proteins | Target RNA | Target sites | Functions | Possible mechanism | Features | Reference |
|---|---|---|---|---|---|---|
QKI | Single strand RNA | QKI binding sites in flanking introns of circRNA-forming exon | Positive | Bringing the flanking introns into vicinity to facilitate the circularization | Inserting QKI binding sites into the adjacent introns of exons appropriately would facilitate the formation of circRNAs instead of mRNAs formed canonically | [62] |
MBL | Single strand RNA | MBL binding sites in flanking introns of circRNA-forming exon | Positive | Bringing the flanking introns into vicinity to facilitate the circularization | Generation of circRNAs compete with canonical cotranscriptional linear splicing; Mbl promote the circMbl at the expense of linear splicing; efficient MBL-induced circularization depends more on the binding of MBL to both introns simultaneously than on the total number of MBL binding sites | [60] |
FUS | Single strand RNA | FUS binging sites in introns flanking the back-splicing junctions | Positive/negative | Through protein-protein and RNA-protein complexes | FUS regulate the biogenesis of circRNA independent of the cognate linear RNA; nuclear located circRNAs facilitated by FUS were consisted of entirely of exonic sequences | [66] |
HNRNPL | Single strand RNA | HNRNPL binding sites in flanking introns of circRNA-forming exon | Positive/negative | HNRNPL binding on both sides of flanking introns presented stronger promoting effect on circRNA formation than on one side; more binding sites correlated with elevated chances to form circRNA | HNRNPL regulate the biogenesis of circRNA independent of the cognate linear RNA; among the circRNAs regulated by HNRNPL, upregulated circRNAs were related to HNRNPL binding more intensely than downregulated circRNAs if the binding occured at flanking introns or within the circRNAs | [67] |
RBM20 | Single strand RNA | RBM20-binding sites in the introns flanking the titin circRNAs | Positive | Provide the substrate to form RBM20-dependent circRNAs post-transcriptionally by excluding specific exons from the pre-mRNA | As RBM20 is the splicing factor responsible for alternative splicing within the I-band of the titin gene, it is crucial for the formation of circRNAs originated from the I-band (ie, Ig and PEVK domain) | [69] |
hnRNPs and SR | Single strand RNA | Specific binding sites in flanking introns | Positive/negative | Probably through aiding or blocking spliceosome assembly | The effects of hnRNPs, and SR proteins were coordinated with the effect of intronic repeats in a combinatorial manner | [70] |
ADAR1 | Double strand RNA | Basepaired dsRNA proximal to the splice sites of circularized exons | Negative | Destroy the paired intronic sequences through A-to-I editing | CircRNAs could be upregualted independently of the expression level of the linear mRNA through ADAR1 depletion | |
DHX9 | Double strand RNA | Long dsRNA formed by base pairing Alu elements | Negative | Might break the paired intronic sequences through resolving inverted-repeat Alu elements | DHX9 exists a synergistic effect with ADAR on circRNA production | [71] |
NF90/NF110 | Double strand RNA | Transient dsRNAs duplexes formed by circRNA-flanking cis complementary sequences | Positive | Stabilizing flanking intronic RNA pairs to promote circRNA processing | NF90 selectively bound to flanking introns of circularized exons and NF90 preferred to bind clusters of A-rich or U-rich sequences, most of which located Alus in introns | [59] |