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Cell Res. 2017 May;27(5):626-641. doi: 10.1038/cr.2017.31. Epub 2017 Mar 10.

Extensive translation of circular RNAs driven by N6-methyladenosine.

Yang Y1,2,3,4, Fan X2, Mao M4,5, Song X2,4, Wu P6,7, Zhang Y8, Jin Y1, Yang Y5, Chen LL8, Wang Y9, Wong CC6,7, Xiao X3, Wang Z2,4.

Author information

1
Institute of Biochemistry, College of Life Sciences, Zhejiang University at Zijingang, Zhejiang, Hangzhou, Zhejiang 310058, China.
2
CAS Key Lab for Computational Biology, CAS Center for Excellence in Molecular Cell Science, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
3
Department of Integrative Biology and Physiology and the Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA.
4
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
5
Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
6
National Center for Protein Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
7
Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China.
8
Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
9
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, China.

Abstract

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 N6-methyladenosine (m6A), the most abundant base modification of RNA, promotes efficient initiation of protein translation from circRNAs in human cells. We discover that consensus m6A motifs are enriched in circRNAs and a single m6A site is sufficient to drive translation initiation. This m6A-driven translation requires initiation factor eIF4G2 and m6A 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 m6A-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.

PMID:
28281539
PMCID:
PMC5520850
DOI:
10.1038/cr.2017.31
[Indexed for MEDLINE]
Free PMC Article

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