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

By Yu-fei He, Bin-zhong Li, Zheng Li, P. Liu, Yang Wang, Qingyu Tang, Jianping Ding, Yingying Jia, Zhangcheng Chen, Lin Li and 7 more. Science, 2011

2,662 citations recorded by the source corpus.

Evidence for a possible route for DNA demethylation in animals is suggested. 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.

Subfields: Molecular Biology, Pediatrics, Perinatology and Child Health

View Paper: https://www.semanticscholar.org/paper/b28ea3d06936c75b1ad58b8f68c1129a25418acc

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. Yi Zhang
2. Hao Wu
3. Chuan He
4. Wolf Reik
5. Craig B. Thompson
6. Manel Esteller
7. W. Kaelin
8. K. Helin

In Pediatrics, Perinatology and Child Health

1. Jörn Walter
2. Yi Zhang
3. Wolf Reik
4. Hao Wu
5. E. Li

Citations in the corpus

• Metabolic regulation of epigenetics (2012, background): “The only difference is that in this reaction, the hydroxymethyl group is a stable product and further TET-dependent modification is undertaken with low stoichiometry (He et al., 2011; Ito et al., 2011).”
• ALKBH5 Is a Mammalian RNA Demethylase that Impacts RNA Metabolism and Mouse Fertility (2012, background): “The recent discoveries of demethylases that actively remove methylations in DNA and histones provide a dynamic picture of mammalian gene expression regulation through reversible methylation (He et al., 2011; Ito et al., 2011; Shi et al., 2004; Tahiliani et al., 2009; Tsukada et al., 2006).”
• Role of TET enzymes in DNA methylation, development, and cancer (2016, background): “Subsequent to the discovery of oxidized 5mC bases, it was demonstrated that TDG has no effect on 5hmC but shows robust recruitment and in vitro catalytic activity toward 5fC and 5caC (He et al. 2011; Maiti and Drohat 2011; Spruijt et al. 2013).”
• Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials (2019, background): “These two molecules can be excised by thymine-DNA glycosylase (TDG) and eventually be repaired to unmodified C.(84) DNA demethylation or restoration of the unmodified cytosine can also occur passively through replication-dependent dilution of 5mC.”
• Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. (2013, positive): “fC and caC can subsequently serve as substrates for thymine-DNA glycosylase (Tdg), which eventually results in the generation of a nonmethylated cytosine (He et al., 2011; Maiti and Drohat, 2011).”
• Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions (2014, positive): “While TDG cannot efficiently remove 5mC or 5hmC, it exhibits robust in vitro excision activity toward 5fC or 5caC (5fC,G or 5caC,G pairs) in duplex DNA (He et al., 2011; Maiti and Drohat, 2011).”
• Influence of Metabolism on Epigenetics and Disease (2013, positive): “TET proteins can oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formyl cytosine (5fC), and 5-carboxylcytosine (5caC) (He et al., 2011; Ito et al., 2011; Tahiliani et al., 2009).”
• WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation (2015, positive): “The wild-type TET2CD converted all 5mC and 5hmC to 5caC as seen by the loss of both 5mC and 5hmC after reaction, while the catalytic mutant (CM) TET2CD that harbors two mutations disrupting binding with Fe2+(He et al., 2011; Ito et al., 2011; Tahiliani et al., 2009) and control HA precipitates from ”
• RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation (2015, background): “FTO is associated with human obesity (Dina et al. 2007; Frayling et al. 2007; Loos and Yeo 2014) and mental development (Hess et al. 2013), while ALKBH5 is shown to affect mouse spermatogenesis in a demethylation-dependent manner (Zheng et al. 2013), suggesting broad roles of m6A in various…”
• Clonal hematopoiesis in human aging and disease (2019, positive): “TET2 is one of three enzymes responsible for catalyzing the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine and further intermediates, which can eventually lead to demethylation (49, 50).”