Efficient backsplicing produces translatable circular mRNAs

By Yang Wang, Zefeng Wang. RNA: A publication of the RNA Society, 2015

622 citations recorded by the source corpus.

While the human transcriptome contains a large number of circular RNAs (circRNAs), the functions of most circRNAs remain unclear. Sequence annotation suggests that most circRNAs are generated from splicing in reversed orders across exons. However, the mechanisms of this backsplicing are largely unknown. Here we constructed a single exon minigene containing split GFP, and found that the pre-mRNA indeed produces circRNA through efficient backsplicing in human and Drosophila cells. The backsplicing is enhanced by complementary introns that form double-stranded RNA structure to bring splice sites in proximity, but such structure is not required. Moreover, backsplicing is regulated by general splicing factors and cis-elements, but with regulatory rules distinct from canonical splicing. The resulting circRNA can be translated to generate functional proteins. Unlike linear mRNA, poly-adenosine or poly-thymidine in 3′ UTR can inhibit circular mRNA translation. This study revealed that backsplicing can occur efficiently in diverse eukaryotes to generate circular mRNAs.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e7affee0044206b1c19ac36d1e9f4dc35c82d955

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In Molecular Biology

Citations in the corpus

Circbank: a comprehensive database for circRNA with standard nomenclature (2019, background): “It has been reported engineered circRNAs can be translatable when containing IRES element [35 – 37].”
Circ-ZNF609 Is a Circular RNA that Can Be Translated and Functions in Myogenesis (2017, background): “Although there are reports of circRNA in vitro translation (Chen and Sarnow, 1995) and of proteins derived from artificial circRNA constructs (Wang and Wang, 2015; Abe et al., 2015), our data demonstrate that an eukaryotic endogenous circRNA may encode for a protein.”
Detecting circular RNAs: bioinformatic and experimental challenges (2016, background): “In fact, such artefacts can dominate the results for some genes, with specific examples suggesting that these artefacts can account for 34–55% of the isoforms detected, sometimes with specific artefactual isoforms detected at higher levels than any of the truly expressed isoforms 44 .”
Non-coding RNAs in disease: from mechanisms to therapeutics (2023, positive): “Recent studies showed that, similar to miRNAs and lncRNAs, some circRNAs can also be translated into proteins 92,93 .”
Past, present, and future of circRNAs (2019, positive): “Additional evidence of IRES-mediated translation of circRNAs in vitro (Chen & Sarnow, 1998) and in cell culture experiments (Wang & Wang, 2015) was previously reported.”
Diverse alternative back-splicing and alternative splicing landscape of circular RNAs (2016, positive): “…is catalyzed, though inefficiently (Zhang et al. 2016), by the canonical spliceosomal machinery (Ashwal-Fluss et al. 2014; Starke et al. 2015; Wang and Wang 2015) and modulated by both cis -elements and trans -factors (Ashwal-Fluss et al. 2014; Zhang et al. 2014; Conn et al. 2015; Ivanov et…”
Novel Role of FBXW7 Circular RNA in Repressing Glioma Tumorigenesis (2017, background): “Interestingly, synthetic circRNAs can also encode peptides or proteins (18,19).”