G/T mismatch-specific thymine DNA glycosylase is an enzyme that in humans is encoded by the TDGgene.[1][2][3] Several bacterial proteins have strong sequence homology with this protein.[4]
The protein encoded by this gene belongs to the TDG/mug DNA glycosylase family. Thymine-DNA glycosylase (TDG) removes thymine moieties from G/T mismatches by hydrolyzing the carbon-nitrogen bond between the sugar-phosphate backbone of DNA and the mispaired thymine. With lower activity, this enzyme also removes thymine from C/T and T/T mispairings. TDG can also remove uracil and 5-bromouracil from mispairings with guanine. TDG knockout mouse models showed no increase in mispairing frequency suggesting that other enzymes, like the functional homologue MBD4, may provide functional redundancy. This gene may have a pseudogene in the p arm of chromosome 12.[3]
Additionally, in 2011, the human thymine DNA glycosylase (hTDG) was reported to efficiently excises 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), the key oxidation products of 5-methylcytosine in genomic DNA.[5] Later on, the crystal structure of the hTDG catalytic domain in complex with duplex DNA containing 5caC was published, which supports the role of TDG in mammalian 5-methylcytosine demethylation.[6]
Interactions
Thymine-DNA glycosylase has been shown to interact with:
↑Gallinari P, Jiricny J (October 1996). "A new class of uracil-DNA glycosylases related to human thymine-DNA glycosylase". Nature. 383 (6602): 735–8. doi:10.1038/383735a0. PMID8878487.
↑Tini M, Benecke A, Um SJ, Torchia J, Evans RM, Chambon P (February 2002). "Association of CBP/p300 acetylase and thymine DNA glycosylase links DNA repair and transcription". Mol. Cell. 9 (2): 265–77. doi:10.1016/S1097-2765(02)00453-7. PMID11864601.
↑Chen D, Lucey MJ, Phoenix F, Lopez-Garcia J, Hart SM, Losson R, Buluwela L, Coombes RC, Chambon P, Schär P, Ali S (October 2003). "T:G mismatch-specific thymine-DNA glycosylase potentiates transcription of estrogen-regulated genes through direct interaction with estrogen receptor alpha". J. Biol. Chem. 278 (40): 38586–92. doi:10.1074/jbc.M304286200. PMID12874288.
↑Takahashi H, Hatakeyama S, Saitoh H, Nakayama KI (February 2005). "Noncovalent SUMO-1 binding activity of thymine DNA glycosylase (TDG) is required for its SUMO-1 modification and colocalization with the promyelocytic leukemia protein". J. Biol. Chem. 280 (7): 5611–21. doi:10.1074/jbc.M408130200. PMID15569683.
↑Minty A, Dumont X, Kaghad M, Caput D (November 2000). "Covalent modification of p73alpha by SUMO-1. Two-hybrid screening with p73 identifies novel SUMO-1-interacting proteins and a SUMO-1 interaction motif". J. Biol. Chem. 275 (46): 36316–23. doi:10.1074/jbc.M004293200. PMID10961991.
Neddermann P, Jiricny J (1993). "The purification of a mismatch-specific thymine-DNA glycosylase from HeLa cells". J. Biol. Chem. 268 (28): 21218–24. PMID8407958.
Barrett TE, Savva R, Panayotou G, et al. (1998). "Crystal structure of a G:T/U mismatch-specific DNA glycosylase: mismatch recognition by complementary-strand interactions". Cell. 92 (1): 117–29. doi:10.1016/S0092-8674(00)80904-6. PMID9489705.
Missero C, Pirro MT, Simeone S, et al. (2001). "The DNA glycosylase T:G mismatch-specific thymine DNA glycosylase represses thyroid transcription factor-1-activated transcription". J. Biol. Chem. 276 (36): 33569–75. doi:10.1074/jbc.M104963200. PMID11438542.
Tini M, Benecke A, Um SJ, et al. (2002). "Association of CBP/p300 acetylase and thymine DNA glycosylase links DNA repair and transcription". Mol. Cell. 9 (2): 265–77. doi:10.1016/S1097-2765(02)00453-7. PMID11864601.
Abu M, Waters TR (2003). "The main role of human thymine-DNA glycosylase is removal of thymine produced by deamination of 5-methylcytosine and not removal of ethenocytosine". J. Biol. Chem. 278 (10): 8739–44. doi:10.1074/jbc.M211084200. PMID12493755.
Chen D, Lucey MJ, Phoenix F, et al. (2003). "T:G mismatch-specific thymine-DNA glycosylase potentiates transcription of estrogen-regulated genes through direct interaction with estrogen receptor alpha". J. Biol. Chem. 278 (40): 38586–92. doi:10.1074/jbc.M304286200. PMID12874288.
Lehner B, Semple JI, Brown SE, et al. (2004). "Analysis of a high-throughput yeast two-hybrid system and its use to predict the function of intracellular proteins encoded within the human MHC class III region". Genomics. 83 (1): 153–67. doi:10.1016/S0888-7543(03)00235-0. PMID14667819.
Brandenberger R, Wei H, Zhang S, et al. (2005). "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation". Nat. Biotechnol. 22 (6): 707–16. doi:10.1038/nbt971. PMID15146197.
Krześniak M, Butkiewicz D, Samojedny A, et al. (2005). "Polymorphisms in TDG and MGMT genes - epidemiological and functional study in lung cancer patients from Poland". Ann. Hum. Genet. 68 (Pt 4): 300–12. doi:10.1046/j.1529-8817.2004.00079.x. PMID15225156.
