title: N6-methyladenosine-dependent regulation of messenger RNA stability.
abstract: N(6)-methyladenosine (m(6)A) is the most prevalent internal (non-cap) modification present in the messenger RNA of all higher eukaryotes. Although essential to cell viability and development, the exact role of m(6)A modification remains to be determined. The recent discovery of two m(6)A demethylases in mammalian cells highlighted the importance of m(6)A in basic biological functions and disease. Here we show that m(6)A is selectively recognized by the human YTH domain family 2 (YTHDF2) 'reader' protein to regulate mRNA degradation. We identified over 3,000 cellular RNA targets of YTHDF2, most of which are mRNAs, but which also include non-coding RNAs, with a conserved core motif of G(m(6)A)C. We further establish the role of YTHDF2 in RNA metabolism, showing that binding of YTHDF2 results in the localization of bound mRNA from the translatable pool to mRNA decay sites, such as processing bodies. The carboxy-terminal domain of YTHDF2 selectively binds to m(6)A-containing mRNA, whereas the amino-terminal domain is responsible for the localization of the YTHDF2-mRNA complex to cellular RNA decay sites. Our results indicate that the dynamic m(6)A modification is recognized by selectively binding proteins to affect the translation status and lifetime of mRNA.
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Zhike
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Gomez
authors.affiliation: Ludwig Institute for Cancer Research, Department of Cellular and Molecular Medicine, UCSD Moores Cancer Center and Institute of Genome Medicine, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0653, USA.
authors.forename: Gary C
authors.initials: GC
authors.lastname: Hon
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Yue
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Dali
authors.initials: D
authors.lastname: Han
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Biochemistry and Molecular Biology and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Parisien
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Dai
authors.affiliation: 1] Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA [2] Department of Chemical Biology and Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
authors.forename: Guifang
authors.initials: G
authors.lastname: Jia
authors.affiliation: Ludwig Institute for Cancer Research, Department of Cellular and Molecular Medicine, UCSD Moores Cancer Center and Institute of Genome Medicine, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0653, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Ren
authors.affiliation: Department of Biochemistry and Molecular Biology and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Pan
authors.affiliation: Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.
authors.forename: Chuan
authors.initials: C
authors.lastname: He
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D015778:Minor Histocompatibility Antigens; D059372:Nucleotide Motifs; D015388:Organelles / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D014176:Protein Biosynthesis; D020871:RNA Stability / Q000187:drug effects; D034443:RNA Transport; D012333:RNA, Messenger / Q000737:chemistry* / Q000378:metabolism*; D022661:RNA, Untranslated / Q000737:chemistry / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000145:classification / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D004268:DNA-Binding Proteins; D015778:Minor Histocompatibility Antigens; D012333:RNA, Messenger; D022661:RNA, Untranslated; D016601:RNA-Binding Proteins; C088203:SON protein, human; C585900:YTHDF2 protein, human; C010223:N-methyladenosine; D000241:Adenosine