title: Extensive translation of circular RNAs driven by N6-methyladenosine.
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.
authors.affiliation: Institute of Biochemistry, College of Life Sciences, Zhejiang University at Zijingang, Zhejiang, Hangzhou, Zhejiang 310058, China.|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.|Department of Integrative Biology and Physiology and the Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA.|Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.|Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
authors.forename: Miaowei
authors.initials: M
authors.lastname: Mao
authors.affiliation: 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.|Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Song
authors.affiliation: National Center for Protein Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.|Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.affiliation: Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Biochemistry, College of Life Sciences, Zhejiang University at Zijingang, Zhejiang, Hangzhou, Zhejiang 310058, China.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Chen
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: National Center for Protein Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.|Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China.
authors.forename: Catherine Cl
authors.initials: CC
authors.lastname: Wong
authors.affiliation: Department of Integrative Biology and Physiology and the Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA.
authors.forename: Xinshu
authors.initials: X
authors.lastname: Xiao
authors.affiliation: 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.|Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Zefeng
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism; D039621:Eukaryotic Initiation Factor-3 / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D059372:Nucleotide Motifs / Q000235:genetics; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D014176:Protein Biosynthesis; D012313:RNA / Q000378:metabolism*; D000079962:RNA, Circular; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D059467:Transcriptome / Q000235:genetics
chemical_list: D039621:Eukaryotic Initiation Factor-3; D039603:Eukaryotic Initiation Factor-4G; D010455:Peptides; D000079962:RNA, Circular; D012333:RNA, Messenger; D012313:RNA; C010223:N-methyladenosine; D000241:Adenosine