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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.

Original publication

DOI

10.1126/science.1210944

Type

Journal article

Journal

Science

Publication Date

02/09/2011

Volume

333

Pages

1303 - 1307

Keywords

5-Methylcytosine, Animals, Cell Line, Cytosine, DNA, DNA Methylation, DNA-Binding Proteins, Embryonic Stem Cells, HEK293 Cells, Humans, Induced Pluripotent Stem Cells, Mice, Oxidation-Reduction, Proto-Oncogene Proteins, RNA, Small Interfering, Thymine DNA Glycosylase, Transfection