title: Tet3 Reads 5-Carboxylcytosine through Its CXXC Domain and Is a Potential Guardian against Neurodegeneration.
abstract: We report that the mammalian 5-methylcytosine (5mC) oxidase Tet3 exists as three major isoforms and characterized the full-length isoform containing an N-terminal CXXC domain (Tet3FL). This CXXC domain binds to unmethylated CpGs, but, unexpectedly, its highest affinity is toward 5-carboxylcytosine (5caC). We determined the crystal structure of the CXXC domain-5caC-DNA complex, revealing the structural basis of the binding specificity of this domain as a reader of CcaCG sequences. Mapping of Tet3FL in neuronal cells shows that Tet3FL is localized precisely at the transcription start sites (TSSs) of genes involved in lysosome function, mRNA processing, and key genes of the base excision repair pathway. Therefore, Tet3FL may function as a regulator of 5caC removal by base excision repair. Active removal of accumulating 5mC from the TSSs of genes coding for lysosomal proteins by Tet3FL in postmitotic neurons of the brain may be important for preventing neurodegenerative diseases.
authors.affiliation: Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA; Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors.forename: Seung-Gi
authors.initials: SG
authors.lastname: Jin
authors.affiliation: Department of Biochemistry, University of California, Riverside, Riverside, CA 92521, USA.
authors.forename: Zhi-Min
authors.initials: ZM
authors.lastname: Zhang
authors.affiliation: Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Dunwell
authors.affiliation: Department of Biochemistry, University of California, Riverside, Riverside, CA 92521, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Harter
authors.affiliation: Department of Molecular and Cellular Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors.forename: Xiwei
authors.initials: X
authors.lastname: Wu
authors.affiliation: Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Johnson
authors.affiliation: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Neurosciences, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors.forename: Jiancheng
authors.initials: J
authors.lastname: Liu
authors.affiliation: Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA; Department of Molecular and Cellular Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors.forename: Piroska E
authors.initials: PE
authors.lastname: Szabó
authors.affiliation: Department of Neurosciences, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Lu
authors.affiliation: The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Guo-Liang
authors.initials: GL
authors.lastname: Xu
authors.affiliation: Department of Biochemistry, University of California, Riverside, Riverside, CA 92521, USA. Electronic address: jikui.song@ucr.edu.
authors.forename: Jikui
authors.initials: J
authors.lastname: Song
authors.affiliation: Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA; Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA. Electronic address: gerd.pfeifer@vai.org.
authors.forename: Gerd P
authors.initials: GP
authors.lastname: Pfeifer
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D018360:Crystallography, X-Ray; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019175:DNA Methylation; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases; D005260:Female; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D024363:Transcription Initiation Site; D014981:Xenopus / Q000378:metabolism
chemical_list: C560974:5-carboxylcytosine; D004268:DNA-Binding Proteins; D006657:Histones; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D003596:Cytosine; D049308:Dioxygenases; C551915:Tet3 protein, mouse