Abstract
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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Acknowledgements
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).
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Supplementary Box 1
Glossary
- RNase R
-
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.
- Cassette exons
-
Exons present in one RNA transcript but absent in an isoform of the transcript.
- Alu elements
-
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.
- A-to-I editing
-
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.
- R-loops
-
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
-
Large autocatalytic ribozymes that catalyse their own excision from mRNA, tRNA and ribosomal RNA precursors.
- Pattern recognition receptor
-
Cellular protein that recognizes pathogenic molecules and confers protection against viral infection by eliciting innate immunity responses.
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Chen, LL. The expanding regulatory mechanisms and cellular functions of circular RNAs. Nat Rev Mol Cell Biol 21, 475–490 (2020). https://doi.org/10.1038/s41580-020-0243-y
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DOI: https://doi.org/10.1038/s41580-020-0243-y
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