Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA

Yu Fei He, Bin Zhong Li, Zheng Li, Peng Liu, Yang Wang, Qingyu Tang, Jianping Ding, Yingying Jia, Zhangcheng Chen, N. Li, Yan Sun, Xiuxue Li, Qing Dai, Chun Xiao Song, Kangling Zhang, Chuan He, Guo Liang Xu

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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.

Original languageEnglish (US)
Pages (from-to)1303-1307
Number of pages5
JournalScience
Volume333
Issue number6047
DOIs
StatePublished - Sep 2 2011
Externally publishedYes

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He, Y. F., Li, B. Z., Li, Z., Liu, P., Wang, Y., Tang, Q., Ding, J., Jia, Y., Chen, Z., Li, N., Sun, Y., Li, X., Dai, Q., Song, C. X., Zhang, K., He, C., & Xu, G. L. (2011). Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science, 333(6047), 1303-1307. https://doi.org/10.1126/science.1210944