G/T mismatch-specific thymine DNA glycosylase

Definition:

DNA glycosylase that plays a key role in active DNA demethylation: specifically recognizes and binds 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) in the context of CpG sites and mediates their excision through base-excision repair (BER) to install an unmethylated cytosine. Cannot remove 5-hydroxymethylcytosine (5hmC). According to an alternative model, involved in DNA demethylation by mediating DNA glycolase activity toward 5-hydroxymethyluracil (5hmU) produced by deamination of 5hmC. Also involved in DNA repair by acting as a thymine-DNA glycosylase that mediates correction of G/T mispairs to G/C pairs: in the DNA of higher eukaryotes, hydrolytic deamination of 5-methylcytosine to thymine leads to the formation of G/T mismatches. Its role in the repair of canonical base damage is however minor compared to its role in DNA demethylation. It is capable of hydrolyzing the carbon-nitrogen bond between the sugar-phosphate backbone of the DNA and a mispaired thymine. In addition to the G/T, it can remove thymine also from C/T and T/T mispairs in the order G/T >> C/T > T/T. It has no detectable activity on apyrimidinic sites and does not catalyze the removal of thymine from A/T pairs or from single-stranded DNA. It can also remove uracil and 5-bromouracil from mispairs with guanine.

References:

[1]. Liang Zhang, et al. Thymine DNA glycosylase specifically recognizes 5-carboxylcytosine-modified DNA. Nat Chem Biol. 2012 Feb 12;8(4):328-30. [Content Brief]

[2]. P Neddermann, et al. Cloning and expression of human G/T mismatch-specific thymine-DNA glycosylase. J Biol Chem. 1996 May 31;271(22):12767-74. [Content Brief]

[3]. P Neddermann, et al. The purification of a mismatch-specific thymine-DNA glycosylase from HeLa cells. J Biol Chem. 1993 Oct 5;268(28):21218-24. [Content Brief]

[4]. P Neddermann, et al. Efficient removal of uracil from G.U mispairs by the mismatch-specific thymine DNA glycosylase from HeLa cells. Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1642-6. [Content Brief]

[5]. Atanu Maiti, et al. Lesion processing by a repair enzyme is severely curtailed by residues needed to prevent aberrant activity on undamaged DNA. Proc Natl Acad Sci U S A. 2012 May 22;109(21):8091-6. [Content Brief]

[6]. Atanu Maiti, et al. Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: potential implications for active demethylation of CpG sites. J Biol Chem. 2011 Oct 14;286(41):35334-35338. [Content Brief]

[7]. Hideharu Hashimoto, et al. Excision of 5-hydroxymethyluracil and 5-carboxylcytosine by the thymine DNA glycosylase domain: its structural basis and implications for active DNA demethylation. Nucleic Acids Res. 2012 Nov 1;40(20):10203-14. [Content Brief]

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