The role of SRSF3 splicing factor in generating circular RNAs

Abstract

Circular RNAs (circRNAs) represent a novel class of non-coding RNAs that are emerging as potentially important regulators of gene expression. circRNAs are typically generated from host gene transcripts through a non-canonical back-splicing mechanism, whose regulation is still not well understood. To explore regulation of circRNAs in cancer, we generated sequence data from RNase R-resistant transcripts in human p493-6 B-lymphoid cells and identified thousands of novel as well as previously identified circRNAs. Approximately 40% of expressed genes generated a circRNA, with half of them generating multiple isoforms, suggesting the involvement of alternative back-splicing and regulatory RNA-binding proteins (RBPs). We observed that genes generating circRNAs with back-spliced exonic junctions were enriched for RBP recognition motifs, including multiple splicing factors, most notably SRSF3, a splicing factor known to promote exon inclusion. To test the role of SRSF3 role in circRNA production, we performed traditional RNA-seq in p493-6 B-lymphoid cells with and without SRSF3 knockdown, and identified 926 mRNA transcripts, whose canonical splicing was affected by SRSF3. We found that a subset (205) of these SRSF3 targets served as host transcripts for circRNA, suggesting that SRSF3 may regulate exon circularization. Since this splicing factor is deregulated in hematologic malignancies, we hypothesize that SRSF3-dependent circRNAs, similar to their mRNA counterparts, might contribute to the pathogenesis of lymphomas and leukemias.

CircRNAs: biogenesis, functions, and role in drug-resistant Tumours

“…In addition, base pairing between Alu elements and dimerization of RBPs in introns play essential regulatory roles in the formation of circRNAs alternative splicing [33,42]. For example, the protein HQK is encoded by quaking (QKI) [43], fused in sarcoma (FUS) [44], and serine/arginine-rich splicing factor 3 (SRSF3) [45]. Via the Mini gene reporting system constructed in Drosophila cells, Liang et al found that the trans splicing factor SR protein and heterogeneous nuclear ribonucleoproteins (hnRNPs) could interact with intron repeat sequences.…”

The Roles of CircRNAs in Regulating Muscle Development of Livestock Animals

“…Besides this, the RNA binding protein (RBP) is an important factor in regulating the production of circRNA. RBP can specifically bind to the flanking introns at both ends of RNA, acting as an RBP while narrowing the distance between the splice recipient and the donor, resulting in the formation of circRNAs (Naqvi et al, 2019; with U1 small nuclear ribonucleoproteins and then increase the transcription of their host genes by binding with RNA pol II; ciRNA, and the RNA pol II complex can directly interact and play a role in regulating parental gene transcription. (e) CircRNAs can be translated into peptides or proteins.…”

“…Besides this, the RNA binding protein (RBP) is an important factor in regulating the production of circRNA. RBP can specifically bind to the flanking introns at both ends of RNA, acting as an RBP while narrowing the distance between the splice recipient and the donor, resulting in the formation of circRNAs ( Naqvi et al, 2019 ; Pagliarini et al, 2020 ; Zhao et al, 2020 ). It is well-known that CDR1as, as an antisense transcript of cerebellar degeneration associated protein 1, can be used as a specific circRNA of miR-7, so it is also known as CIRS-7.…”