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

doi:10.1126/science.1210944

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 language	English (US)
Pages (from-to)	1303-1307
Number of pages	5
Journal	Science
Volume	333
Issue number	6047
DOIs	https://doi.org/10.1126/science.1210944
State	Published - Sep 2 2011
Externally published	Yes

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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.",

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

year = "2011",

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doi = "10.1126/science.1210944",

language = "English (US)",

volume = "333",

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T1 - Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA

AU - He, Yu Fei

AU - Li, Bin Zhong

AU - Li, Zheng

AU - Liu, Peng

AU - Wang, Yang

AU - Tang, Qingyu

AU - Ding, Jianping

AU - Jia, Yingying

AU - Chen, Zhangcheng

AU - Li, N.

AU - Sun, Yan

AU - Li, Xiuxue

AU - Dai, Qing

AU - Song, Chun Xiao

AU - Zhang, Kangling

AU - He, Chuan

AU - Xu, Guo Liang

PY - 2011/9/2

Y1 - 2011/9/2

N2 - 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.

AB - 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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EP - 1307

JO - Science

JF - Science

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

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