HGNC Approved Gene Symbol: TDG
Cytogenetic location: 12q23.3 Genomic coordinates (GRCh38): 12:103,965,872-103,988,874 (from NCBI)
The process of spontaneous hydrolytic deamination affects all DNA bases with exocyclic amino groups (Lindahl, 1982). Hydrolytic deamination of 5-methylcytosine leads to the formation of G/T mismatches. These G/T mismatches are corrected to G/C basepairs by a mismatch-specific DNA-binding glycosylase, TDG.
Neddermann et al. (1996) cloned a human cDNA for TDG. They found 2 distinct cDNA species that differed by 100 nucleotides at the 3-prime untranslated region. These cDNAs encode a 410-amino acid, 46-kD polypeptide. Both in vitro- and E. coli-expressed TDG migrated in denaturing polyacrylamide gels with an apparent size of 60 kD. Database searches identified a mouse cDNA sequence that encodes a murine TDG homolog. No common amino acid sequence motifs could be found between the G/T-specific enzyme and other DNA glycosylases, suggesting to Neddermann et al. (1996) that TDG belongs to a novel class of base-excision repair enzymes.
Sard et al. (1997) showed by Northern blot analysis that TDG is expressed at approximately the same level in all human tissues analyzed.
TDG initiates repair of G/T and G/U mismatches, commonly associated with CpG islands, by removing thymine and uracil moieties. Tini et al. (2002) reported that TDG associates with transcriptional coactivators CBP (600140) and p300 (602700) and that the resulting complexes are competent for both the excision step of repair and histone acetylation. TDG stimulated CBP transcriptional activity in transfected cells and reciprocally served as a substrate for CBP/p300 acetylation. This acetylation triggered release of CBP from DNA ternary complexes and also regulated recruitment of repair endonuclease APE (107748). These observations revealed a potential regulatory role for protein acetylation in base mismatch repair and a role for CBP/p300 in maintaining genomic stability.
He et al. (2011) demonstrated that 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in DNA are oxidized to 5-carboxylcytosine (5caC) by Tet dioxygenases (see 607790) in vitro and in cultured cells. 5caC is specifically recognized and excised by TDG. Depletion of TDG in mouse embryonic stem cells leads to accumulation of 5caC to a readily detectable level. He et al. (2011) concluded that oxidation of 5mC by Tet proteins followed by TDG-mediated base excision of 5caC constitutes a pathway for active DNA demethylation.
Crystal Structure
Barrett et al. (1998) studied the crystal structure of MUG (mismatch-specific uracil DNA-glycosylase), the E. coli homolog of human TDG, and that of a DNA complex. Their analysis of the crystal structures explained the thymine-DNA glycosylase activity and the specificity for G:U/T mispairs.
Baba et al. (2005) reported the crystal structure of the central region of human TDG conjugated to SUMO1 (601912) at 2.1-angstrom resolution. The structure revealed a helix protruding from the protein surface, which presumably interferes with the product DNA and thus promotes the dissociation of TDG from the DNA molecule. This helix is formed by covalent and noncovalent contacts between TDG and SUMO1. The noncovalent contacts are also essential for release from the product DNA, as verified by mutagenesis.
Sard et al. (1997) characterized the intron/exon boundaries of a portion of the TDG gene contained within a genomic clone and identified a CA dinucleotide repeat in 1 intron.
De Gregorio et al. (1996) mapped the Tdg gene to mouse chromosome 10 and a pseudogene to mouse chromosome 4. The functional gene maps to a region homologous to human 9p22-qter.
By fluorescence in situ hybridization, Sard et al. (1997) localized 3 different TDG-related genomic clones to chromosome 12. PCR and sequence analyses revealed that only 1, localized at 12q24.1, contained the coding gene.
Cortazar et al. (2011) attempted to generate Tdg-knockout mice, but no homozygous-null mutants were born alive. In timed matings, Tdg-null embryos isolated up to embryonic day 10.5 appeared alive and normal, whereas those isolated at embryonic day 12.5 were dead, and none were detectable at embryonic day 16.5. Tdg-null embryos at embryonic day 10.5 produced viable fibroblasts, but only a third of embryonic day 11.5 embryos did so, suggesting that by this stage most of them were dead. Cortazar et al. (2011) identified internal hemorrhage as the cause of death. Tdg-null embryos are associated with epigenetic aberrations affecting the expression of developmental genes. Fibroblasts derived from Tdg-null embryos (mouse embryonic fibroblasts) showed impaired gene regulation coincident with imbalanced histone modification and CpG methylation at promoters of affected genes. TDG associates with the promoters of such genes both in fibroblasts and in embryonic stem cells, but epigenetic aberrations appear only upon cell lineage commitment. Cortazar et al. (2011) showed that TDG contributes to the maintenance of active and bivalent chromatin throughout cell differentiation, facilitating a proper assembly of chromatin-modifying complexes and initiating base excision repair to counter aberrant de novo methylation. Cortazar et al. (2011) concluded that TDG-dependent DNA repair has evolved to provide epigenetic stability in lineage-committed cells.
Baba, D., Maita, N., Jee, J.-G., Uchimura, Y., Saitoh, H., Sugasawa, K., Hanaoka, F., Tochio, H., Hiroaki, H., Shirakawa, M. Crystal structure of thymine DNA glycosylase conjugated to SUMO-1. (Letter) Nature 435: 979-982, 2005. [PubMed: 15959518] [Full Text: https://doi.org/10.1038/nature03634]
Barrett, T. E., Savva, R., Panayotou, G., Barlow, T., Brown, T., Jiricny, J., Pearl, L. H. Crystal structure of a G:T/U mismatch-specific DNA glycosylase: mismatch recognition by complementary-strand interactions. Cell 92: 117-129, 1998. [PubMed: 9489705] [Full Text: https://doi.org/10.1016/s0092-8674(00)80904-6]
Cortazar, D., Kunz, C., Selfridge, J., Lettieri, T., Saito, Y., MacDougall, E., Wirz, A., Schuermann, D., Jacobs, A. L., Siegrist, F., Steinacher, R., Jiricny, J., Bird, A., Schar, P. Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability. Nature 470: 419-423, 2011. [PubMed: 21278727] [Full Text: https://doi.org/10.1038/nature09672]
De Gregorio, L., Gallinari, P., Gariboldi, M., Manenti, G., Pierotti, M. A., Jiricny, J., Dragani, T. A. Genetic mapping of thymine DNA glycosylase (Tdg) gene and of one pseudogene in the mouse. Mammalian Genome 7: 909-910, 1996. [PubMed: 8995763] [Full Text: https://doi.org/10.1007/s003359900267]
He, Y.-F., Li, B.-Z., Li, Z., Liu, P., Wang, Y., Tang, Q., Ding, J., Jia, Y., Chen, Z., Li, L., Sun, Y., Li, X., Dai, Q., Song, C.-X., Zhang, K., He, C., Xu, G.-L. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333: 1303-1307, 2011. [PubMed: 21817016] [Full Text: https://doi.org/10.1126/science.1210944]
Lindahl, T. DNA repair enzymes. Ann. Rev. Biochem. 51: 61-87, 1982. [PubMed: 6287922] [Full Text: https://doi.org/10.1146/annurev.bi.51.070182.000425]
Neddermann, P., Gallinari, P., Lettieri, T., Schmid, D., Truong, O., Hsuan, J. J., Wiebauer, K., Jiricny, J. Cloning and expression of human G/T mismatch-specific thymine-DNA glycosylase. J. Biol. Chem. 271: 12767-12774, 1996. [PubMed: 8662714] [Full Text: https://doi.org/10.1074/jbc.271.22.12767]
Sard, L., Tornielli, S., Gallinari, P., Minoletti, F., Jiricny, J., Lettieri, T., Pierotti, M. A., Sozzi, G., Radice, P. Chromosomal localizations and molecular analysis of TDG gene-related sequences. Genomics 44: 222-226, 1997. [PubMed: 9299239] [Full Text: https://doi.org/10.1006/geno.1997.4843]
Tini, M., Benecke, A., Um, S.-J., Torchia, J., Evans, R. M., Chambon, P. Association of CBP/p300 acetylase and thymine DNA glycosylase links DNA repair and transcription. Molec. Cell 9: 265-277, 2002. [PubMed: 11864601] [Full Text: https://doi.org/10.1016/s1097-2765(02)00453-7]