2. Academic Validation
  3. Extensive translation of circular RNAs driven by N6-methyladenosine

Extensive translation of circular RNAs driven by N6-methyladenosine

  • Cell Res. 2017 May;27(5):626-641. doi: 10.1038/cr.2017.31.
Yun Yang 1 2 3 4,  Xiaojuan Fan 2,  Miaowei Mao 4 5,  Xiaowei Song 2 4,  Ping Wu 6 7,  Yang Zhang 8,  Yongfeng Jin 1,  Yi Yang 5,  Ling-Ling Chen 8,  Yang Wang 9,  Catherine Cl Wong 6 7,  Xinshu Xiao 3,  Zefeng Wang 2 4
Affiliations

Affiliations

  • 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.
PMID: 28281539 DOI: 10.1038/cr.2017.31
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.

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