Thymine-DNA glycosylase

TDG
Available structures PDB Human UniProt search: PDBe RCSB List of PDB id codes 1WYW, 2D07, 2RBA, 3UFJ, 3UO7, 3UOB, 4FNC, 4JGC, 4XEG, 4Z3A, 4Z47, 4Z7B, 4Z7Z, 5CYS
Identifiers
Aliases	TDG , hThymine-DNA glycosylase, thymine DNA glycosylase
External IDs	OMIM: 601423; MGI: 3645587; HomoloGene: 2415; GeneCards: TDG; OMA:TDG - orthologs
Gene location (Human) Chr. Chromosome 12 (human) [1] Band 12q23.3 Start 103,965,822 bp [1] End 103,988,874 bp [1]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in buccal mucosa cell visceral pleura tibia endothelial cell epithelium of nasopharynx gingival epithelium parietal pleura amniotic fluid germinal epithelium hair follicle n/a More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein homodimerization activity transcription coregulator activity damaged DNA binding protein binding double-stranded DNA binding hydrolase activity protein kinase C binding transcription factor binding DNA N-glycosylase activity mismatched DNA binding protein domain specific binding DNA binding magnesium ion binding uracil DNA N-glycosylase activity ATP binding pyrimidine-specific mismatch base pair DNA N-glycosylase activity sodium ion binding chloride ion binding SUMO binding protein self-association G/U mismatch-specific uracil-DNA glycosylase activity Cellular component PML body plasma membrane nucleoplasm nucleus Biological process regulation of transcription, DNA-templated embryo development negative regulation of chromatin binding oxidative DNA demethylation negative regulation of transcription by RNA polymerase II negative regulation of protein binding transcription, DNA-templated cellular response to DNA damage stimulus depyrimidination DNA demethylation base-excision repair DNA repair DNA mismatch repair regulation of gene expression, epigenetic base-excision repair, AP site formation regulation of DNA N-glycosylase activity chromatin organization regulation of embryonic development Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6996 545124 Ensembl ENSG00000139372 n/a UniProt Q13569 n/a RefSeq (mRNA) NM_001008411 NM_003211 NM_001363612 XM_006521630 RefSeq (protein) NP_003202 NP_001350541 n/a Location (UCSC) Chr 12: 103.97 – 103.99 Mb n/a PubMed search [2] [3]
Wikidata
View/Edit Human View/Edit Mouse

G/T mismatch-specific thymine DNA glycosylase is an enzyme that in humans is encoded by the TDG gene. ^{[4] [5] [6]} Several bacterial proteins have strong sequence homology with this protein. ^[7]

Function

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. ^[6]

Additionally, in 2011, the human thymine DNA glycosylase (hTDG) was reported to efficiently excise 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), the key oxidation products of 5-methylcytosine in genomic DNA. ^[8] 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. ^[9]

Interactions

Thymine-DNA glycosylase has been shown to interact with:

• CREB-binding protein, ^[10]
• Estrogen receptor alpha, ^[11]
• Promyelocytic leukemia protein, ^[12]
• SUMO3, ^[13] and
• Small ubiquitin-related modifier 1. ^{[13] [14]}

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. ^{[§ 1]}

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|alt=Fluorouracil (5-FU) Activity edit]]

Fluorouracil (5-FU) Activity edit

1. The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601".

See also

• DNA-deoxyinosine glycosylase
• SMUG1
• Uracil-DNA glycosylase
• MBD4

References

1. GRCh38: Ensembl release 89: ENSG00000139372 – Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. Neddermann P, Gallinari P, Lettieri T, Schmid D, Truong O, Hsuan JJ, Wiebauer K, Jiricny J (August 1996). "Cloning and expression of human G/T mismatch-specific thymine-DNA glycosylase". J Biol Chem. 271 (22): 12767–74. doi: 10.1074/jbc.271.22.12767 . PMID   8662714.
5. Sard L, Tornielli S, Gallinari P, Minoletti F, Jiricny J, Lettieri T, Pierotti MA, Sozzi G, Radice P (December 1997). "Chromosomal localizations and molecular analysis of TDG gene-related sequences". Genomics. 44 (2): 222–6. doi:10.1006/geno.1997.4843. PMID   9299239.
6. "Entrez Gene: TDG thymine-DNA glycosylase".
7. Gallinari P, Jiricny J (October 1996). "A new class of uracil-DNA glycosylases related to human thymine-DNA glycosylase". Nature. 383 (6602): 735–8. Bibcode:1996Natur.383..735G. doi:10.1038/383735a0. PMID   8878487. S2CID   4235485.
8. He YF, Li BZ, Li Z, Liu P, Wang Y, Tang Q, Ding J, Jia Y, Chen Z, Li L, Sun Y, Li X, Dai Q, Song CX, Zhang K, He C, Xu GL (September 2011). "Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA". Science. 333 (6047): 1303–7. Bibcode:2011Sci...333.1303H. doi:10.1126/science.1210944. PMC   3462231 . PMID   21817016.
9. Zhang L, Lu X, Lu J, Liang H, Dai Q, Xu GL, Luo C, Jiang H, He C (February 2012). "Thymine DNA glycosylase specifically recognizes 5-carboxylcytosine-modified DNA". Nature Chemical Biology. 8 (4): 328–30. doi:10.1038/nchembio.914. PMC   3307914 . PMID   22327402.
10. 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 . PMID   11864601.
11. 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 . PMID   12874288.
12. 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 . PMID   15569683.
13. Hardeland U, Steinacher R, Jiricny J, Schär P (March 2002). "Modification of the human thymine-DNA glycosylase by ubiquitin-like proteins facilitates enzymatic turnover". EMBO J. 21 (6): 1456–64. doi:10.1093/emboj/21.6.1456. PMC   125358 . PMID   11889051.
14. 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 . PMID   10961991.

Further reading

• Lindahl T (1982). "DNA repair enzymes". Annu. Rev. Biochem. 51: 61–87. doi: 10.1146/annurev.bi.51.070182.000425 . PMID   6287922.
• Hardeland U, Bentele M, Lettieri T, et al. (2001). "Thymine DNA glycosylase". Base Excision Repair. Progress in Nucleic Acid Research and Molecular Biology. Vol. 68. pp. 235–53. doi:10.1016/S0079-6603(01)68103-0. ISBN   978-0-12-540068-8. PMID   11554300.{{cite book}}: |journal= ignored (help)
• Chevray PM, Nathans D (1992). "Protein interaction cloning in yeast: identification of mammalian proteins that react with the leucine zipper of Jun". Proc. Natl. Acad. Sci. U.S.A. 89 (13): 5789–93. Bibcode:1992PNAS...89.5789C. doi: 10.1073/pnas.89.13.5789 . PMC   402103 . PMID   1631061.
• Neddermann P, Jiricny J (1994). "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. 91 (5): 1642–6. doi: 10.1073/pnas.91.5.1642 . PMC   43219 . PMID   8127859.
• Neddermann P, Jiricny J (1993). "The purification of a mismatch-specific thymine-DNA glycosylase from HeLa cells". J. Biol. Chem. 268 (28): 21218–24. doi: 10.1016/S0021-9258(19)36913-3 . PMID   8407958.
• 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 . PMID   9489705. S2CID   9136303.
• 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 . PMID   11438542.
• 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 . PMID   11864601.
• Hardeland U, Steinacher R, Jiricny J, Schär P (2002). "Modification of the human thymine-DNA glycosylase by ubiquitin-like proteins facilitates enzymatic turnover". EMBO J. 21 (6): 1456–64. doi:10.1093/emboj/21.6.1456. PMC   125358 . PMID   11889051.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi: 10.1073/pnas.242603899 . PMC   139241 . PMID   12477932.
• 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 . PMID   12493755.
• Shimizu Y, Iwai S, Hanaoka F, Sugasawa K (2003). "Xeroderma pigmentosum group C protein interacts physically and functionally with thymine DNA glycosylase". EMBO J. 22 (1): 164–73. doi:10.1093/emboj/cdg016. PMC   140069 . PMID   12505994.
• 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 . PMID   12874288.
• 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. PMID   14667819.
• 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. PMID   15146197. S2CID   27764390.
• 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. PMID   15225156. S2CID   35293833.
• He YF, Li BZ, Li Z, Liu P, Wang Y, Tang Q, Ding J, Jia Y, Chen Z, Li L, Sun Y, Li X, Dai Q, Song CX, Zhang K, He C, Xu GL (September 2011). "Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA". Science. 333 (6047): 1303–7. Bibcode:2011Sci...333.1303H. doi:10.1126/science.1210944. PMC   3462231 . PMID   21817016.
• Zhang L, Lu X, Lu J, Liang H, Dai Q, Xu GL, Luo C, Jiang H, He C (February 2012). "Thymine DNA glycosylase specifically recognizes 5-carboxylcytosine-modified DNA". Nature Chemical Biology. 8 (4): 328–30. doi:10.1038/nchembio.914. PMC   3307914 . PMID   22327402.
• Xu J, Cortellino S, Tricarico R, Chang WC, Scher G, Devarajan K, Slifker M, Moore R, Bassi MR, Caretti E, Clapper M, Cooper H, Bellacosa A (September 2017). "Thymine DNA Glycosylase (TDG) is involved in the pathogenesis of intestinal tumors with reduced APC expression". Oncotarget. 8 (52): 89988–89997. doi:10.18632/oncotarget.21219. PMC   5685726 . PMID   29163805.