nature reviews molecular cell biology
Many protein-coding genes in higher eukaryotes can produce circular RNAs (circRNAs) through back-splicing of exons. CircRNAs differ from mRNAs in their production, structure and turnover and thereby have unique cellular functions and potential biomedical applications. In this Review, I discuss recent progress in our understanding of the biogenesis of circRNAs and the regulation of their abundance and of their biological functions, including in transcription and splicing, sequestering or scaffolding of macromolecules to interfere with microRNA activities or signalling pathways, and serving as templates for translation. I further discuss the emerging roles of circRNAs in regulating immune responses and cell proliferation, and the possibilities of applying circRNA technologies in biomedical research.
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Fig. 1: Back-splicing and alternative (back-) splicing in the formation of circular RNAs.
Fig. 2: Regulation of back-splicing efficiency.
Fig. 3: Nuclear export and degradation of circular RNAs.
Fig. 4: Molecular mechanisms of circular RNA function.
Fig. 5: Cellular and physiological roles of circular RNAs.
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The author apologizes to colleagues whose work is not discussed here owing to space limitations. The author thanks L. Yang, C.-X. Liu, X. Li and S.-K. Guo for discussions. This work was supported by grants from the Chinese Academy of Sciences (XDB19020104), the National Natural Science Foundation of China (91940303, 31725009, 31821004, 31861143025) and the HHMI International Research Scholar Program (55008728).
State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
School of Life Science and Technology, ShanghaiTech University, Shanghai, China
The author declares no competing interests.
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Supplementary Box 1
A 3′-to-5′ exonuclease that preferentially digests linear RNAs, thereby allowing the enrichment of circular RNAs.
Internal ribosome entry site
(IRES). A structural RNA element that makes possible the initiation of cap-independent translation.
Spliceosomal E complex
Formation of this complex initiates the splicing cycle and is crucial for the accurate definition of introns and exons by the splicing machinery.
Exons present in one RNA transcript but absent in an isoform of the transcript.
Primate-specific retrotransposons that constitute almost 11% of the human genome.
Exon definition complexes
Protein complexes that initially recognize splice sites and direct prespliceosome assembly on exons. They further interact across long introns to form the catalytic spliceosome.
In higher eukaryotes, the predominant form of RNA modification, in which adenosine is modified to inosine within imperfect double-stranded RNAs.
Nonsense-mediated mRNA decay
A mechanism of selective degradation of mRNAs; a means of post-transcriptional gene regulation in mammals.
Triple-stranded nucleic acid structures that form during transcription; they consist of a DNA–RNA hybrid and the single-stranded non-template DNA.
Group I introns