Tet-Mediated Formation of 5-Carboxylcytosine and Its Excision by TDG in Mammalian DNA

Yufei He(Center for Excellence in Molecular Cell Science), Bin-Zhong Li(Center for Excellence in Molecular Cell Science), Zheng Li(Center for Excellence in Molecular Cell Science), Peng Liu(Center for Excellence in Molecular Cell Science), Yang Wang(Center for Excellence in Molecular Cell Science), Qingyu Tang(Chinese Academy of Sciences), Jianping Ding(Chinese Academy of Sciences), Yingying Jia(Chinese Academy of Sciences), Zhangcheng Chen(Chinese Academy of Sciences), Lin Li(Chinese Academy of Sciences), Yan Sun(Chinese Academy of Sciences), Xiuxue Li(Chinese Academy of Sciences), Qing Dai(University of Chicago), Chun‐Xiao Song(University of Chicago), Kangling Zhang(Loma Linda University), Chuan He(University of Chicago), Guoliang Xu(Center for Excellence in Molecular Cell Science)
Science
August 4, 2011
10.1126/science.1210944
Cited by 2,752

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.

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