Thymine DNA Glycosylase Can Rapidly Excise 5-Formylcytosine and 5-Carboxylcytosine
By A. Maiti, A. Drohat. Journal of Biological Chemistry, 2011
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Background: Thymine DNA glycosylase is essential for active DNA demethylation and embryonic development. Results: TDG rapidly excises 5-formylcytosine (fC) and 5-carboxylcytosine (caC), products of Tet-mediated oxidation of 5-methylcytosine. Conclusion: Excision of fC and caC is consistent with TDG specificity for removing modified C or mC from CpG sites. Significance: The results suggest that active DNA demethylation could involve TDG excision of Tet-produced fC (or caC) and subsequent BER. Thymine DNA glycosylase (TDG) excises T from G·T mispairs and is thought to initiate base excision repair (BER) of deaminated 5-methylcytosine (mC). Recent studies show that TDG, including its glycosylase activity, is essential for active DNA demethylation and embryonic development. These and other findings suggest that active demethylation could involve mC deamination by a deaminase, giving a G·T mispair followed by TDG-initiated BER. An alternative proposal is that demethylation could involve iterative oxidation of mC to 5-hydroxymethylcytosine (hmC) and then to 5-formylcytosine (fC) and 5-carboxylcytosine (caC), mediated by a Tet (ten eleven translocation) enzyme, with conversion of caC to C by a putative decarboxylase. Our previous studies suggest that TDG could excise fC and caC from DNA, which could provide another potential demethylation mechanism. We show here that TDG rapidly removes fC, with higher activity than for G·T mispairs, and has substantial caC excision activity, yet it cannot remove hmC. TDG excision of fC and caC, oxidation products of mC, is consistent with its strong specificity for excising bases from a CpG context. Our findings reveal a remarkable new aspect of specificity for TDG, inform its catalytic mechanism, and suggest that TDG could protect against fC-induced mutagenesis. The results also suggest a new potential mechanism for active DNA demethylation, involving TDG excision of Tet-produced fC (or caC) and subsequent BER. Such a mechanism obviates the need for a decarboxylase and is consistent with findings that TDG glycosylase activity is essential for active demethylation and embryonic development, as are mechanisms involving TDG excision of deaminated mC or hmC.
Subfields: Molecular Biology, Virology
View Paper: https://www.semanticscholar.org/paper/9e5058b0b9e8fbb1b169ed074e841c66fda02a2e
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Citations in the corpus
- Base-Resolution Analysis of 5-Hydroxymethylcytosine in the Mammalian Genome (2012, positive): “…process of DNA demethylation, either passively (Inoue and Zhang, 2011), or actively through further oxidation (He et al., 2011; Ito et al., 2011; Maiti and Drohat, 2011; Zhang et al., 2012); 2) 5hmC may be recognized by chromatin factors (Frauer et al., 2011; Yildirim et al., 2011), and that…”
- Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. (2013, positive): “One of the proteins that binds to fC and caC, but not to hmC, is Tdg, which is consistent with its reported substrate specificity (Maiti and Drohat, 2011).”
- Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. (2011, background): “Recurrent somatic mutations of IDH1/2 are frequently found in glioma and AML patients (Parsons et al. 2008; Mardis et al. 2009; Yan et al. 2009; Gross et al. 2010; Marcucci et al. 2010; Ward et al. 2010).”
- 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).”