thymine dna glycosylase

Summary

Summary: An enzyme that removes THYMINE and URACIL bases mispaired with GUANINE through hydrolysis of their N-glycosidic bond. These mispaired nucleotides generally occur through the hydrolytic DEAMINATION of 5-METHYLCYTOSINE to thymine.

Top Publications

  1. Hashimoto H, Liu Y, Upadhyay A, Chang Y, Howerton S, Vertino P, et al. Recognition and potential mechanisms for replication and erasure of cytosine hydroxymethylation. Nucleic Acids Res. 2012;40:4841-9 pubmed publisher
    ..We further show that the deamination product of 5hmC could be excised by thymine DNA glycosylase and MBD4 glycosylases regardless of context.
  2. Boland M, Christman J. Characterization of Dnmt3b:thymine-DNA glycosylase interaction and stimulation of thymine glycosylase-mediated repair by DNA methyltransferase(s) and RNA. J Mol Biol. 2008;379:492-504 pubmed publisher
    ..G mismatch repair efficiency upon loss of DNA methyltransferase expression, as well as a requirement for an RNA component for correct T.G mismatch repair. ..
  3. Lutsenko E, Bhagwat A. The role of the Escherichia coli mug protein in the removal of uracil and 3,N(4)-ethenocytosine from DNA. J Biol Chem. 1999;274:31034-8 pubmed
    ..coli that can remove this mutagenic adduct. Thus, the principal role of Mug in E. coli may be to help repair damage to DNA caused by exogenous chemical agents such as chloroacetaldehyde. ..
  4. Barrett T, Schärer O, Savva R, Brown T, Jiricny J, Verdine G, et al. Crystal structure of a thwarted mismatch glycosylase DNA repair complex. EMBO J. 1999;18:6599-609 pubmed
  5. He Y, Li B, Li Z, Liu P, Wang Y, Tang Q, et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science. 2011;333:1303-7 pubmed publisher
    ..These data suggest that oxidation of 5mC by Tet proteins followed by TDG-mediated base excision of 5caC constitutes a pathway for active DNA demethylation. ..
  6. Liu P, Theruvathu J, Darwanto A, Lao V, Pascal T, Goddard W, et al. Mechanisms of base selection by the Escherichia coli mispaired uracil glycosylase. J Biol Chem. 2008;283:8829-36 pubmed publisher
    ..The presence of a series of glycosylases that focus on different lesion properties, all coexisting within the same cell, would provide a robust and partially redundant repair system necessary for the maintenance of the genome. ..
  7. Morgan M, Bennett M, Drohat A. Excision of 5-halogenated uracils by human thymine DNA glycosylase. Robust activity for DNA contexts other than CpG. J Biol Chem. 2007;282:27578-86 pubmed
    b>Thymine DNA glycosylase (TDG) excises thymine from G.T mispairs and removes a variety of damaged bases (X) with a preference for lesions in a CpG.X context...
  8. Métivier R, Gallais R, Tiffoche C, Le Péron C, Jurkowska R, Carmouche R, et al. Cyclical DNA methylation of a transcriptionally active promoter. Nature. 2008;452:45-50 pubmed publisher
    ..Cyclical changes in the methylation status of promoter CpGs may thus represent a critical event in transcriptional achievement. ..
  9. Morgan M, Maiti A, Fitzgerald M, Drohat A. Stoichiometry and affinity for thymine DNA glycosylase binding to specific and nonspecific DNA. Nucleic Acids Res. 2011;39:2319-29 pubmed publisher
    ..b>Thymine DNA glycosylase (TDG) removes thymine from these G · T lesions, and follow-on base excision repair yields a G · C pair...

More Information

Publications62

  1. Li S, Huang Q, Wang L, Lan Y, Zhang X, Yang B, et al. A convenient spectrometric assay system for intracellular quantitative measurement of DNA glycosylase activity. Acta Biochim Biophys Sin (Shanghai). 2010;42:381-7 pubmed
    ..b>Thymine DNA glycosylase and methyl-CpG-binding protein 4 are major DNA glycosylases involved in the mismatch repair progress, and ..
  2. Kunz C, Focke F, Saito Y, Schuermann D, Lettieri T, Selfridge J, et al. Base excision by thymine DNA glycosylase mediates DNA-directed cytotoxicity of 5-fluorouracil. PLoS Biol. 2009;7:e91 pubmed publisher
    ..In this study, we investigated a possible role of thymine DNA glycosylase (TDG), one of four mammalian uracil DNA glycosylases (UDGs), in the cellular response to 5-FU...
  3. Bennett M, Rodgers M, Hebert A, Ruslander L, Eisele L, Drohat A. Specificity of human thymine DNA glycosylase depends on N-glycosidic bond stability. J Am Chem Soc. 2006;128:12510-9 pubmed
    ..While some DNA glycosylases exhibit narrow specificity, others remove multiple forms of damage. Human thymine DNA glycosylase (hTDG) cleaves thymine from mutagenic G...
  4. Cortázar D, Kunz C, Selfridge J, Lettieri T, Saito Y, MacDougall E, et al. Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability. Nature. 2011;470:419-23 pubmed publisher
    b>Thymine DNA glycosylase (TDG) is a member of the uracil DNA glycosylase (UDG) superfamily of DNA repair enzymes...
  5. Mohan R, Rao A, Gagliardi J, Tini M. SUMO-1-dependent allosteric regulation of thymine DNA glycosylase alters subnuclear localization and CBP/p300 recruitment. Mol Cell Biol. 2007;27:229-43 pubmed
    Previous studies have demonstrated that the base excision repair enzyme thymine DNA glycosylase (TDG) mediates recruitment of histone acetyltransferases CREB-binding protein (CBP) and p300 to DNA, suggesting a plausible role for these ..
  6. Li Y, Zhou P, Zheng X, Walsh C, Xu G. Association of Dnmt3a and thymine DNA glycosylase links DNA methylation with base-excision repair. Nucleic Acids Res. 2007;35:390-400 pubmed
    ..In mammals, two repair enzymes, thymine DNA glycosylase (TDG) and methyl-CpG binding domain 4 (MBD4), have evolved to counteract the mutagenic effect of ..
  7. Hashimoto H, Zhang X, Cheng X. Activity and crystal structure of human thymine DNA glycosylase mutant N140A with 5-carboxylcytosine DNA at low pH. DNA Repair (Amst). 2013;12:535-40 pubmed publisher
    The mammalian thymine DNA glycosylase (TDG) excises 5-carboxylcytosine (5caC) when paired with a guanine in a CpG sequence, in addition to mismatched bases...
  8. Talhaoui I, Couv S, Ishchenko A, Kunz C, Sch r P, Saparbaev M. 7,8-Dihydro-8-oxoadenine, a highly mutagenic adduct, is repaired by Escherichia coli and human mismatch-specific uracil/thymine-DNA glycosylases. Nucleic Acids Res. 2013;41:912-23 pubmed publisher
    ..coli, we demonstrate that the excision of 8oxoA from 8oxoA•T and 8oxoA•G has an absolute requirement for TDG and MUG, respectively. The data establish that MUG and TDG can counteract the genotoxic effects of 8oxoA residues in vivo...
  9. Maiti A, Noon M, MacKerell A, Pozharski E, Drohat A. 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;109:8091-6 pubmed publisher
    ..A key player is thymine DNA glycosylase (TDG), which excises thymine from mutagenic G·T mispairs that arise by deamination of 5-methylcytosine (..
  10. Zhang W, Liu Z, Crombet L, Amaya M, Liu Y, Zhang X, et al. Crystal structure of the mismatch-specific thymine glycosylase domain of human methyl-CpG-binding protein MBD4. Biochem Biophys Res Commun. 2011;412:425-8 pubmed publisher
    ..But the different residues in the N-terminal of domain result in the change of charge distribution on the surface of the protein, which suggest the different roles that may relate some diseases. ..
  11. Doseth B, Visnes T, Wallenius A, Ericsson I, Sarno A, Pettersen H, et al. Uracil-DNA glycosylase in base excision repair and adaptive immunity: species differences between man and mouse. J Biol Chem. 2011;286:16669-80 pubmed publisher
    ..Our results reveal significant species differences in genomic uracil processing. These findings should be taken into account when mouse models are used in studies of uracil DNA repair and adaptive immunity. ..
  12. Peng B, Hurt E, Hodge D, Thomas S, Farrar W. DNA hypermethylation and partial gene silencing of human thymine- DNA glycosylase in multiple myeloma cell lines. Epigenetics. 2006;1:138-45 pubmed
    ..Hypermethylation of DNA damage repair genes in MM cell lines may provide an explanation for the frequent genomic instability, as well as point mutations, that are encountered in MM. ..
  13. Maiti A, Drohat A. Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: potential implications for active demethylation of CpG sites. J Biol Chem. 2011;286:35334-8 pubmed publisher
    b>Thymine DNA glycosylase (TDG) excises T from G·T mispairs and is thought to initiate base excision repair (BER) of deaminated 5-methylcytosine (mC)...
  14. Lucey M, Chen D, Lopez Garcia J, Hart S, Phoenix F, Al Jehani R, et al. T:G mismatch-specific thymine-DNA glycosylase (TDG) as a coregulator of transcription interacts with SRC1 family members through a novel tyrosine repeat motif. Nucleic Acids Res. 2005;33:6393-404 pubmed
    ..We have shown previously that the base excision repair enzyme thymine DNA glycosylase (TDG) acts as a potent coactivator for estrogen receptor-alpha...
  15. Cortázar D, Kunz C, Saito Y, Steinacher R, Schär P. The enigmatic thymine DNA glycosylase. DNA Repair (Amst). 2007;6:489-504 pubmed
    When it was first isolated from extracts of HeLa cells in Josef Jiricny's laboratory, the thymine DNA glycosylase (TDG) attracted attention because of its ability to remove thymine, i.e. a normal DNA base, from G.T mispairs...
  16. Fitzgerald M, Drohat A. Coordinating the initial steps of base excision repair. Apurinic/apyrimidinic endonuclease 1 actively stimulates thymine DNA glycosylase by disrupting the product complex. J Biol Chem. 2008;283:32680-90 pubmed publisher
    ..A prominent example is thymine DNA glycosylase (TDG), which removes T from G...
  17. O Neill R, Vorob eva O, Shahbakhti H, Zmuda E, Bhagwat A, Baldwin G. Mismatch uracil glycosylase from Escherichia coli: a general mismatch or a specific DNA glycosylase?. J Biol Chem. 2003;278:20526-32 pubmed
    ..glycosylase (MUG) was identified in the Escherichia coli genome as a sequence homolog of the mammalian thymine DNA glycosylase, with activity against uracil in U.G mismatches...
  18. Zhou J, Blue E, Hu G, Herring B. Thymine DNA glycosylase represses myocardin-induced smooth muscle cell differentiation by competing with serum response factor for myocardin binding. J Biol Chem. 2008;283:35383-92 pubmed publisher
    ..From this screen, thymine DNA glycosylase (TDG) was identified as a myocardin-associated protein...
  19. Maiti A, Morgan M, Pozharski E, Drohat A. Crystal structure of human thymine DNA glycosylase bound to DNA elucidates sequence-specific mismatch recognition. Proc Natl Acad Sci U S A. 2008;105:8890-5 pubmed publisher
    ..T mispairs, which are implicated in genetic disease, cancer, and aging. Human thymine DNA glycosylase (hTDG) removes T from G...
  20. Krokan H, Drabløs F, Slupphaug G. Uracil in DNA--occurrence, consequences and repair. Oncogene. 2002;21:8935-48 pubmed
    ..Studies are now underway to examine whether mice deficient in Ung develop lymphoproliferative malignancies and have a different life span. ..
  21. Maiti A, Morgan M, Drohat A. Role of two strictly conserved residues in nucleotide flipping and N-glycosylic bond cleavage by human thymine DNA glycosylase. J Biol Chem. 2009;284:36680-8 pubmed publisher
    b>Thymine DNA glycosylase (TDG) promotes genomic integrity by excising thymine from mutagenic G.T mismatches arising by deamination of 5-methylcytosine, and follow-on base excision repair enzymes restore a G.C pair...
  22. Xu X, Yu T, Shi J, Chen X, Zhang W, Lin T, et al. Thymine DNA glycosylase is a positive regulator of Wnt signaling in colorectal cancer. J Biol Chem. 2014;289:8881-90 pubmed publisher
    ..While screening a panel of DNA demethylases, we found that thymine DNA glycosylase (TDG) up-regulated Wnt signaling...
  23. Jurado J, Maciejewska A, Krwawicz J, Laval J, Saparbaev M. Role of mismatch-specific uracil-DNA glycosylase in repair of 3,N4-ethenocytosine in vivo. DNA Repair (Amst). 2004;3:1579-90 pubmed
    ..The increased spontaneous mutation rate for G.C --> A.T transition in the ung mug double mutant as compared to the single ung mutant suggest that MUG may be a back-up repair enzyme to the classic uracil-DNA glycosylase. ..
  24. Dong L, Mi R, Glass R, Barry J, Cao W. Repair of deaminated base damage by Schizosaccharomyces pombe thymine DNA glycosylase. DNA Repair (Amst). 2008;7:1962-72 pubmed publisher
    ..The relationship among amino acid substitutions, binding affinity and base recognition is discussed. ..
  25. Guliaev A, Singer B, Hang B. Chloroethylnitrosourea-derived ethano cytosine and adenine adducts are substrates for Escherichia coli glycosylases excising analogous etheno adducts. DNA Repair (Amst). 2004;3:1311-21 pubmed
    ..However, also as shown by MD, the stacking interaction between the EC base and Phe 30 in the Mug active site is reduced as compared to the epsilonC base, which could account for the lower EC activity observed in this study. ..
  26. Morera S, Grin I, Vigouroux A, Couve S, Henriot V, Saparbaev M, et al. Biochemical and structural characterization of the glycosylase domain of MBD4 bound to thymine and 5-hydroxymethyuracil-containing DNA. Nucleic Acids Res. 2012;40:9917-26 pubmed publisher
    ..The recognition mechanism of flipped-out 5hmU bases in MBD4(cat) active site supports the potential role of MBD4, together with TDG, in maintenance of genome stability and active DNA demethylation in mammals. ..
  27. Gallinari P, Jiricny J. A new class of uracil-DNA glycosylases related to human thymine-DNA glycosylase. Nature. 1996;383:735-8 pubmed
  28. Takahashi H, Hatakeyama S, Saitoh H, Nakayama K. 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. 2005;280:5611-21 pubmed
    ..This screening resulted in the isolation of cDNAs encoding the b isoform of thymine DNA glycosylase (TDGb)...
  29. Hardeland U, Kunz C, Focke F, Szadkowski M, Schär P. Cell cycle regulation as a mechanism for functional separation of the apparently redundant uracil DNA glycosylases TDG and UNG2. Nucleic Acids Res. 2007;35:3859-67 pubmed
    ..Thus, TDG- and UNG2-dependent base excision repair alternates throughout the cell cycle, and the ubiquitin-proteasome pathway constitutes the underlying regulatory system. ..
  30. Steinacher R, Schär P. Functionality of human thymine DNA glycosylase requires SUMO-regulated changes in protein conformation. Curr Biol. 2005;15:616-23 pubmed
    ..SUMOylation then reverses this structural change in the product bound TDG. ..
  31. Yoon J, Iwai S, O Connor T, Pfeifer G. Human thymine DNA glycosylase (TDG) and methyl-CpG-binding protein 4 (MBD4) excise thymine glycol (Tg) from a Tg:G mispair. Nucleic Acids Res. 2003;31:5399-404 pubmed
    The repair enzymes thymine DNA glycosylase (TDG) and methyl-CpG-binding protein 4 (MBD4) remove thymines from T:G mismatches resulting from deamination of 5-methylcytosine...
  32. Hashimoto H, Hong S, Bhagwat A, Zhang X, Cheng X. 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;40:10203-14 pubmed publisher
    The mammalian thymine DNA glycosylase (TDG) is implicated in active DNA demethylation via the base excision repair pathway. TDG excises the mismatched base from G:X mismatches, where X is uracil, thymine or 5-hydroxymethyluracil (5hmU)...
  33. Vasovcak P, Krepelova A, Menigatti M, Puchmajerova A, Skapa P, Augustinakova A, et al. Unique mutational profile associated with a loss of TDG expression in the rectal cancer of a patient with a constitutional PMS2 deficiency. DNA Repair (Amst). 2012;11:616-23 pubmed publisher
    ..This case provides the first in vivo evidence of the key role of TDG in protecting the human genome against the deleterious effects of 5-methylcytosine deamination. ..
  34. Cortellino S, Xu J, Sannai M, Moore R, Caretti E, Cigliano A, et al. Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell. 2011;146:67-79 pubmed publisher
    ..Here, we show that either knockout or catalytic inactivation of the DNA repair enzyme thymine DNA glycosylase (TDG) leads to embryonic lethality in mice...
  35. Gros L, Ishchenko A, Saparbaev M. Enzymology of repair of etheno-adducts. Mutat Res. 2003;531:219-29 pubmed
  36. Baba D, Maita N, Jee J, Uchimura Y, Saitoh H, Sugasawa K, et al. Crystal structure of SUMO-3-modified thymine-DNA glycosylase. J Mol Biol. 2006;359:137-47 pubmed
    ..Structural comparison with the canonical SBM shows that this SBM-like sequence of TDG retains all of the characteristic interactions of the SBM, indicating sequence diversity in the SBM. ..
  37. Cortellino S, Turner D, Masciullo V, Schepis F, Albino D, Daniel R, et al. The base excision repair enzyme MED1 mediates DNA damage response to antitumor drugs and is associated with mismatch repair system integrity. Proc Natl Acad Sci U S A. 2003;100:15071-6 pubmed
    ..MED1 defects (much like MMR defects) may impair cell cycle arrest and apoptosis induced by DNA damage. ..
  38. Mokkapati S, Fernandez de Henestrosa A, Bhagwat A. Escherichia coli DNA glycosylase Mug: a growth-regulated enzyme required for mutation avoidance in stationary-phase cells. Mol Microbiol. 2001;41:1101-11 pubmed
    ..Thus, Mug joins a very small coterie of DNA repair enzymes whose principal function is to avoid mutations in stationary-phase cells. ..
  39. Rai K, Huggins I, James S, Karpf A, Jones D, Cairns B. DNA demethylation in zebrafish involves the coupling of a deaminase, a glycosylase, and gadd45. Cell. 2008;135:1201-12 pubmed publisher
    ..Our results provide evidence for a coupled mechanism of 5-meC demethylation, whereby AID deaminates 5-meC, followed by thymine base excision by Mbd4, promoted by Gadd45. ..
  40. Smet Nocca C, Wieruszeski J, Chaar V, Leroy A, Benecke A. The thymine-DNA glycosylase regulatory domain: residual structure and DNA binding. Biochemistry. 2008;47:6519-30 pubmed publisher
    ..T mismatch processing activity of TDG. ..
  41. Maiti A, Drohat A. Dependence of substrate binding and catalysis on pH, ionic strength, and temperature for thymine DNA glycosylase: Insights into recognition and processing of G·T mispairs. DNA Repair (Amst). 2011;10:545-53 pubmed publisher
    ..b>Thymine DNA glycosylase (TDG) is one of two mammalian enzymes that can specifically remove thymine from G·T mispairs...
  42. Pearl L. Structure and function in the uracil-DNA glycosylase superfamily. Mutat Res. 2000;460:165-81 pubmed
  43. Hang B, Guliaev A. Substrate specificity of human thymine-DNA glycosylase on exocyclic cytosine adducts. Chem Biol Interact. 2007;165:230-8 pubmed
    ..These findings expand the TDG substrate range and aid in understanding the structural requirements for TDG substrate specificity. ..
  44. Hang B, Downing G, Guliaev A, Singer B. Novel activity of Escherichia coli mismatch uracil-DNA glycosylase (Mug) excising 8-(hydroxymethyl)-3,N4-ethenocytosine, a potential product resulting from glycidaldehyde reaction. Biochemistry. 2002;41:2158-65 pubmed
    ..We believe that these findings may have biological and structural implications in defining the role of 8-HM-epsilonC in glycosylase recognition/repair. ..
  45. Choi J, Pfeifer G. DNA damage and mutations produced by chloroacetaldehyde in a CpG-methylated target gene. Mutat Res. 2004;568:245-56 pubmed
    ..CAA-induced DNA adducts were mapped along the supF gene by using thermostable thymine DNA glycosylase (TDG) in conjunction with ligation-mediated PCR or by a Taq polymerase stop assay...
  46. Ulrich H. SUMO modification: wrestling with protein conformation. Curr Biol. 2005;15:R257-9 pubmed
  47. Zhang L, Lu X, Lu J, Liang H, Dai Q, Xu G, et al. Thymine DNA glycosylase specifically recognizes 5-carboxylcytosine-modified DNA. Nat Chem Biol. 2012;8:328-30 pubmed publisher
    Human thymine DNA glycosylase (hTDG) efficiently excises 5-carboxylcytosine (5caC), a key oxidation product of 5-methylcytosine in genomic DNA, in a recently discovered cytosine demethylation pathway...
  48. Guan X, Madabushi A, Chang D, Fitzgerald M, Shi G, Drohat A, et al. The human checkpoint sensor Rad9-Rad1-Hus1 interacts with and stimulates DNA repair enzyme TDG glycosylase. Nucleic Acids Res. 2007;35:6207-18 pubmed
    Human (h) DNA repair enzyme thymine DNA glycosylase (hTDG) is a key DNA glycosylase in the base excision repair (BER) pathway that repairs deaminated cytosines and 5-methyl-cytosines...
  49. Mohan R, Litchfield D, Torchia J, Tini M. Opposing regulatory roles of phosphorylation and acetylation in DNA mispair processing by thymine DNA glycosylase. Nucleic Acids Res. 2010;38:1135-48 pubmed publisher
    CpG dinucleotides are mutational hotspots associated with cancer and genetic diseases. Thymine DNA glycosylase (TDG) plays an integral role in CpG maintenance by excising mispaired thymine and uracil in a CpG context and also ..
  50. Missero C, Pirro M, Simeone S, Pischetola M, Di Lauro R. The DNA glycosylase T:G mismatch-specific thymine DNA glycosylase represses thyroid transcription factor-1-activated transcription. J Biol Chem. 2001;276:33569-75 pubmed
    ..for factors that regulate TTF-1 transcriptional activity, we isolated three genes (T:G mismatch-specific thymine DNA glycosylase (TDG), homeodomain-interacting protein kinase 2 (HIPK2), and Ajuba), whose products can interact with TTF-..
  51. Grippon S, Zhao Q, Robinson T, Marshall J, O Neill R, Manning H, et al. Differential modes of DNA binding by mismatch uracil DNA glycosylase from Escherichia coli: implications for abasic lesion processing and enzyme communication in the base excision repair pathway. Nucleic Acids Res. 2011;39:2593-603 pubmed publisher
    ..It therefore provides a new perspective on abasic site protection and the findings are discussed in the context of downstream lesion processing and enzyme communication in the base excision repair pathway. ..
  52. Baba D, Maita N, Jee J, Uchimura Y, Saitoh H, Sugasawa K, et al. Crystal structure of thymine DNA glycosylase conjugated to SUMO-1. Nature. 2005;435:979-82 pubmed
    ..During DNA mismatch repair, SUMO conjugation of the uracil/thymine DNA glycosylase TDG promotes the release of TDG from the abasic (AP) site created after base excision, and coordinates ..
  53. Zhang P, Huang B, Xu X, Sessa W. Ten-eleven translocation (Tet) and thymine DNA glycosylase (TDG), components of the demethylation pathway, are direct targets of miRNA-29a. Biochem Biophys Res Commun. 2013;437:368-73 pubmed publisher
    ..5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which can be further oxidized and repaired by thymine DNA glycosylase (TDG), to influence gene transcription in embryonic and adult tissues...