Extensive translation of circular RNAs driven by N6-methyladenosine
Open accessAbstract
Extensive pre-mRNA back-splicing generates numerous circular RNAs (circRNAs) in human transcriptome. However, the biological functions of these circRNAs remain largely unclear. Here we report that N 6 -methyladenosine (m 6 A), the most abundant base modification of RNA, promotes efficient initiation of protein translation from circRNAs in human cells. We discover that consensus m 6 A motifs are enriched in circRNAs and a single m 6 A site is sufficient to drive translation initiation. This m 6 A-driven translation requires initiation factor eIF4G2 and m 6 A reader YTHDF3, and is enhanced by methyltransferase METTL3/14, inhibited by demethylase FTO, and upregulated upon heat shock. Further analyses through polysome profiling, computational prediction and mass spectrometry reveal that m 6 A-driven translation of circRNAs is widespread, with hundreds of endogenous circRNAs having translation potential. Our study expands the coding landscape of human transcriptome, and suggests a role of circRNA-derived proteins in cellular responses to environmental stress.
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A small number of circRNAs can be translated despite lacking both terminal 5′ and 3′ ends.
“Emerging evidence indicates that a small number of circRNAs can be translated despite lacking both terminal 5 ′ and 3 ′ ends [53,55,56].”
From Circular RNAs in depression: Biogenesis, function, expression, and therapeutic potential (2021) · cites this paper as [55]
CircRNA can be translated by adding the IRES element or m6A modification incorporated to its 5′ UTR region.
“Despite the lack of essential elements for cap-dependent translation, circRNA can be translated by adding the IRES element or m6A modification incorporated to its 5′ UTR region.223,224”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [224]
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“RNA modification with N6-methyladenosine (m6A) has been shown to mediate cap-independent translation in endogenous linear and circRNAs (Meyer et al. 2015; Yang et al. 2017).”
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- Authors
- Yang, Y., Fan, X., Mao, M., Song, X., Wu, P., Zhang, Y., Jin, Y., Yang, Y., Chen, L.-L., Wang, Y., Wong, C. C., Xiao, X., & Wang, Z.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Chinese Academy of Sciences (CN)
- Zhejiang University (CN)
- Dalian Medical University (CN)
- University of California, Los Angeles (US)
- Corresponding author
- Wang, Zefeng
- ORCID
- Venue
- Cell Research
- Published
- 2017-03-10
- Volume
- 27
- Issue
- 5
- Pages
- 626-641
- ISSN
- 1001-0602 (ISSN-L)
- 1748-7838
- PMC
- PMC5520850
- OpenAlex
- W2592988313
- Cited by
- 1,855
- References
- 49
- Citations by year
- 2026: 117 · 2025: 154 · 2024: 210 · 2023: 198 · 2022: 287 · 2021: 305 · 2020: 241 · 2019: 166 · 2018: 122 · 2017: 53
- FWCI
- 65.15
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell Research (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion)
- UNC Libraries
- Funders
- National Natural Science Foundation of China (31570823, 91540110, 31300655)
- National Institutes of Health
- National Human Genome Research Institute (R01HG006264)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Circular RNAs in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- circular RNA, N6-methyladenosine, m6A RNA methylation, circRNA translation, translation initiation, eIF4G2, YTHDF3, heat shock response, polysome profiling, human transcriptome
- MeSH terms
- RNA, Circular, Adenosine, HeLa Cells, Humans, Peptides, RNA, RNA, Messenger, Protein Biosynthesis, Eukaryotic Initiation Factor-4G, Eukaryotic Initiation Factor-3, Tandem Mass Spectrometry, Nucleotide Motifs, Transcriptome
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