title: Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA.
abstract: The prevalent DNA modification in higher organisms is the methylation of cytosine to 5-methylcytosine (5mC), which is partially converted to 5-hydroxymethylcytosine (5hmC) by the Tet (ten eleven translocation) family of dioxygenases. Despite their importance in epigenetic regulation, it is unclear how these cytosine modifications are reversed. Here, we demonstrate that 5mC and 5hmC in DNA are oxidized to 5-carboxylcytosine (5caC) by Tet dioxygenases in vitro and in cultured cells. 5caC is specifically recognized and excised by thymine-DNA glycosylase (TDG). Depletion of TDG in mouse embyronic stem cells leads to accumulation of 5caC to a readily detectable level. These data suggest that oxidation of 5mC by Tet proteins followed by TDG-mediated base excision of 5caC constitutes a pathway for active DNA demethylation.
authors.affiliation: Group of DNA Metabolism, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yu-Fei
authors.initials: YF
authors.lastname: He
authors.forename: Bin-Zhong
authors.initials: BZ
authors.lastname: Li
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Tang
authors.forename: Jianping
authors.initials: J
authors.lastname: Ding
authors.forename: Yingying
authors.initials: Y
authors.lastname: Jia
authors.forename: Zhangcheng
authors.initials: Z
authors.lastname: Chen
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.forename: Xiuxue
authors.initials: X
authors.lastname: Li
authors.forename: Qing
authors.initials: Q
authors.lastname: Dai
authors.forename: Chun-Xiao
authors.initials: CX
authors.lastname: Song
authors.forename: Kangling
authors.initials: K
authors.lastname: Zhang
authors.forename: Chuan
authors.initials: C
authors.lastname: He
authors.forename: Guo-Liang
authors.initials: GL
authors.lastname: Xu
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism / Q000031:analogs & derivatives; D000818:Animals; D002460:Cell Line; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases; D053595:Embryonic Stem Cells; D057809:HEK293 Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D051379:Mice; D010084:Oxidation-Reduction; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D044502:Thymine DNA Glycosylase / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: C560974:5-carboxylcytosine; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C540839:TET1 protein, mouse; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D004247:DNA; D049308:Dioxygenases; C551914:Tet2 protein, mouse; C551915:Tet3 protein, mouse; D044502:Thymine DNA Glycosylase