Thymine-DNA glycosylase explained

G/T mismatch-specific thymine DNA glycosylase is an enzyme that in humans is encoded by the TDG gene.^{[1] [2] [3]} Several bacterial proteins have strong sequence homology with this protein.^[4]

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.

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.^[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:

• CREB-binding protein,^[7]
• Estrogen receptor alpha,^[8]
• Promyelocytic leukemia protein,^[9]
• SUMO3,^[10] and
• Small ubiquitin-related modifier 1.^{[10] [11]}

See also

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

References

Further reading

• Lindahl T. DNA repair enzymes. Annu. Rev. Biochem.. 51. 61–87. 1982. 6287922. 10.1146/annurev.bi.51.070182.000425. free.
• Book: Hardeland U, Bentele M, Lettieri T, etal. Base Excision Repair. Thymine DNA glycosylase. Prog. Nucleic Acid Res. Mol. Biol.. 68. 235–53. 2001. 11554300. 10.1016/S0079-6603(01)68103-0. Progress in Nucleic Acid Research and Molecular Biology. 978-0-12-540068-8.
• Chevray PM, Nathans D. 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. 1992. 1631061. 10.1073/pnas.89.13.5789. 402103. 1992PNAS...89.5789C. free.
• Neddermann P, Jiricny J. 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. 1994. 8127859. 10.1073/pnas.91.5.1642. 43219. free.
• Neddermann P, Jiricny J. The purification of a mismatch-specific thymine-DNA glycosylase from HeLa cells. J. Biol. Chem.. 268. 28. 21218–24. 1993. 10.1016/S0021-9258(19)36913-3. 8407958. free.
• Barrett TE, Savva R, Panayotou G, etal. Crystal structure of a G:T/U mismatch-specific DNA glycosylase: mismatch recognition by complementary-strand interactions. Cell. 92. 1. 117–29. 1998. 9489705. 10.1016/S0092-8674(00)80904-6. 9136303. free.
• Missero C, Pirro MT, Simeone S, etal. The DNA glycosylase T:G mismatch-specific thymine DNA glycosylase represses thyroid transcription factor-1-activated transcription. J. Biol. Chem.. 276. 36. 33569–75. 2001. 11438542. 10.1074/jbc.M104963200. free.
• Tini M, Benecke A, Um SJ, etal. Association of CBP/p300 acetylase and thymine DNA glycosylase links DNA repair and transcription. Mol. Cell. 9. 2. 265–77. 2002. 11864601. 10.1016/S1097-2765(02)00453-7. free.
• Hardeland U, Steinacher R, Jiricny J, Schär P. Modification of the human thymine-DNA glycosylase by ubiquitin-like proteins facilitates enzymatic turnover. EMBO J.. 21. 6. 1456–64. 2002. 11889051. 10.1093/emboj/21.6.1456. 125358.
• Strausberg RL, Feingold EA, Grouse LH, etal. 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. 2003. 12477932. 10.1073/pnas.242603899. 139241. 2002PNAS...9916899M . free.
• Abu M, Waters TR. 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. 2003. 12493755. 10.1074/jbc.M211084200. free.
• Shimizu Y, Iwai S, Hanaoka F, Sugasawa K. Xeroderma pigmentosum group C protein interacts physically and functionally with thymine DNA glycosylase. EMBO J.. 22. 1. 164–73. 2003. 12505994. 10.1093/emboj/cdg016. 140069.
• Chen D, Lucey MJ, Phoenix F, etal. 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. 2003. 12874288. 10.1074/jbc.M304286200. free.
• Lehner B, Semple JI, Brown SE, etal. 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. 2004. 14667819. 10.1016/S0888-7543(03)00235-0.
• Brandenberger R, Wei H, Zhang S, etal. Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation. Nat. Biotechnol.. 22. 6. 707–16. 2005. 15146197. 10.1038/nbt971. 27764390.
• Krześniak M, Butkiewicz D, Samojedny A, etal. Polymorphisms in TDG and MGMT genes - epidemiological and functional study in lung cancer patients from Poland. Ann. Hum. Genet.. 68. Pt 4. 300–12. 2005. 15225156. 10.1046/j.1529-8817.2004.00079.x. 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. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA.. Science. 333. 6047. 1303–7. September 2011. 21817016. 3462231. 10.1126/science.1210944. 2011Sci...333.1303H.
• Zhang L, Lu X, Lu J, Liang H, Dai Q, Xu GL, Luo C, Jiang H, He C. Thymine DNA glycosylase specifically recognizes 5-carboxylcytosine-modified DNA.. Nature Chemical Biology. 8. 4. 328–30. February 2012. 22327402. 3307914. 10.1038/nchembio.914.
• 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. 10.18632/oncotarget.21219. 5685726. 29163805.

Notes and References

1. Neddermann P, Gallinari P, Lettieri T, Schmid D, Truong O, Hsuan JJ, Wiebauer K, Jiricny J . Cloning and expression of human G/T mismatch-specific thymine-DNA glycosylase . J Biol Chem . 271 . 22 . 12767–74 . August 1996 . 8662714 . 10.1074/jbc.271.22.12767 . free .
2. Sard L, Tornielli S, Gallinari P, Minoletti F, Jiricny J, Lettieri T, Pierotti MA, Sozzi G, Radice P . Chromosomal localizations and molecular analysis of TDG gene-related sequences . Genomics . 44 . 2 . 222–6 . December 1997 . 9299239 . 10.1006/geno.1997.4843 .
3. Web site: Entrez Gene: TDG thymine-DNA glycosylase.
4. Gallinari P, Jiricny J . A new class of uracil-DNA glycosylases related to human thymine-DNA glycosylase . Nature . 383 . 6602 . 735–8 . October 1996 . 8878487 . 10.1038/383735a0 . 1996Natur.383..735G . 4235485 .
5. 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 . Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. . Science . 333 . 6047 . 1303–7 . September 2011 . 21817016 . 3462231. 10.1126/science.1210944 . 2011Sci...333.1303H .
6. Zhang L, Lu X, Lu J, Liang H, Dai Q, Xu GL, Luo C, Jiang H, He C . Thymine DNA glycosylase specifically recognizes 5-carboxylcytosine-modified DNA. . Nature Chemical Biology . 8 . 4 . 328–30 . February 2012 . 22327402 . 3307914. 10.1038/nchembio.914 .
7. Tini M, Benecke A, Um SJ, Torchia J, Evans RM, Chambon P . Association of CBP/p300 acetylase and thymine DNA glycosylase links DNA repair and transcription . Mol. Cell . 9 . 2 . 265–77 . February 2002 . 11864601 . 10.1016/S1097-2765(02)00453-7 . free .
8. Chen D, Lucey MJ, Phoenix F, Lopez-Garcia J, Hart SM, Losson R, Buluwela L, Coombes RC, Chambon P, Schär P, Ali S . 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 . October 2003 . 12874288 . 10.1074/jbc.M304286200 . free .
9. Takahashi H, Hatakeyama S, Saitoh H, Nakayama KI . 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 . February 2005 . 15569683 . 10.1074/jbc.M408130200 . free .
10. Hardeland U, Steinacher R, Jiricny J, Schär P . Modification of the human thymine-DNA glycosylase by ubiquitin-like proteins facilitates enzymatic turnover . EMBO J. . 21 . 6 . 1456–64 . March 2002 . 11889051 . 125358 . 10.1093/emboj/21.6.1456 .
11. Minty A, Dumont X, Kaghad M, Caput D . 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 . November 2000 . 10961991 . 10.1074/jbc.M004293200 . free .