Disease relevance of TDG

• Polymorphisms in TDG and MGMT genes - epidemiological and functional study in lung cancer patients from Poland [1].
• Xeroderma pigmentosum group C protein interacts physically and functionally with thymine DNA glycosylase [2].
• No excision of J was found, but 5-HmU was excised by AlkA and Mug from Escherichia coli and by human SMUG1 and TDG, confirming previous reports [3].
• At present, we have found no evidence that TDG is central to the development of gastric cancer, limiting the importance of TDG in T:G mismatch repair and subsequent carcinogenesis [4].
• Thiodiglycol (2,2'-bis-hydroxyethylsulfide, TDG), the hydrolysis product of the chemical warfare agent sulfur mustard, has been implicated in the toxicity of sulfur mustard through the inhibition of protein phosphatases in mouse liver cytosol [5].

High impact information on TDG

• Details of the MUG structure explain its thymine DNA-glycosylase activity and the specificity for G:U/T mispairs, which derives from direct recognition of guanine on the complementary strand [6].
• A corresponding catalytic mechanism could apply to the DNA glycosylases TDG and SMUG1, which belong to the same structural superfamily as UDG [7].
• Thymine DNA glycosylase (TDG) initiates repair of G/T and G/U mismatches, commonly associated with CpG islands, by removing thymine and uracil moieties [8].
• We report that TDG associates with transcriptional coactivators CBP and p300 and that the resulting complexes are competent for both the excision step of repair and histone acetylation [8].
• SUMO conjugation dramatically reduces the DNA substrate and AP site binding affinity of TDG, and this is associated with a significant increase in enzymatic turnover in reactions with a G*U substrate and the loss of G*T processing activity [9].

Chemical compound and disease context of TDG

• In the present experiments, we employed the mesophilic Escherichia coli enzyme deoxyinosine 3'-endonuclease (Endo V), and a novel thermostable T/G DNA glycosylase, TDG mismatch repair enzyme (TDG-MRE) [10].
• The toxicity of other compounds varied between moderate (TDG, mercaptoethanol) to strong (ethanolamine, diisobutyl ester of MPhA) [11].
• The 3,N(4)-ethenocytosine (epsilon C) residue might have biological role in vivo since it is recognized and efficiently excised in vitro by the E. coli mismatch-specific uracil-DNA glycosylase (MUG) and the human thymine-DNA glycosylase (hTDG) [12].

Biological context of TDG

• Furthermore, TDG was found to potentiate CBP/p300-dependent transcription and serve as a substrate for CBP/p300 acetylation [13].
• TDG is an enzyme involved in base excision repair [14].
• Previously, we established that posttranslational modification of TDG with Small Ubiquitin-like MOdifiers (SUMOs) facilitates the dissociation of the DNA glycosylase from the product AP site, but the underlying molecular mechanism remained unclear [15].
• Human thymine-DNA glycosylase (TDG) is a mismatch-specific uracil/thymine-DNA glycosylase with an implicated function in the restoration of G*C base pairs at sites of cytosine or 5-methylcytosine deamination [9].
• SUMO-1-dependent allosteric regulation of thymine DNA glycosylase alters subnuclear localization and CBP/p300 recruitment [13].

Anatomical context of TDG

• TDG-mediated inhibition occurs specifically on TTF-1-responsive promoters in thyroid and non thyroid cells [14].
• Efficient removal of uracil from G.U mispairs by the mismatch-specific thymine DNA glycosylase from HeLa cells [16].
• TDG is highly expressed in thymus and is expressed at lower levels in all human tissues analyzed [4].
• METHODS: Nucleotide sequences of the entire coding region of the TDG gene were analyzed in 21 human pancreatic cancer cell lines. mRNA expression of the TDG gene was also analyzed by Northern hybridization in several human tissues and 21 human pancreatic cancer cell lines [17].
• Enriched mismatch and perfect match cDNA samples from human primary melanoma cells and normal melanocytes were obtained by selection using mismatch repair thymine DNA glycosylase-bound beads [18].

Associations of TDG with chemical compounds

• TDG is also posttranslationally modified by covalent conjugation of SUMO-1 (sumoylation) to lysine 341 [13].
• The parental (A1235) extract, when supplemented with ATP and human thymine DNA glycosylase (TDG), acted proficiently on all three substrates, incising immediately 5' to the mismatched thymine or uracil residue [19].
• Finally, the base 5' to the mismatched G in the G:T mispair conferred sequence preference on the A1235 extract in the presence of ATP and TDG, with a pyrimidine (especially cytosine) being much favored over a purine [19].
• T:G mismatch-specific thymine-DNA glycosylase potentiates transcription of estrogen-regulated genes through direct interaction with estrogen receptor alpha [20].
• The same protein was later found to interact physically and functionally with the retinoid receptors RAR and RXR, and this implicated an unexpected function of TDG in nuclear receptor-mediated transcriptional activation of gene expression [21].

Physical interactions of TDG

• Human thymine DNA glycosylase (TDG) and methyl-CpG-binding protein 4 (MBD4) excise thymine glycol (Tg) from a Tg:G mispair [22].
• We show here that the DNA methyltransferase Dnmt3a interacts with TDG [23].

Other interactions of TDG

• CONCLUSION: Our data provide insight into the molecular mechanism of SUMO modification mediated modulation of enzymatic properties of TDG [15].
• TDG remains bound to this unstable repair intermediate, indicating that its transmission to the downstream-acting AP endonuclease is a coordinated process [15].
• We studied two genes coding for proteins removing small DNA adducts by direct repair (MGMT), or mispaired DNA bases by base excision repair (TDG) [1].
• TDG and MBD4 may have specialized roles in the repair of U and T in mismatches in CpG contexts [24].
• CONCLUSION: We detected novel germline alterations in NEIL2, TDG and UNG patients with CRC [25].

Analytical, diagnostic and therapeutic context of TDG

• Northern blot analysis showed that TDG is expressed at approximately the same level in all human tissues analyzed [26].
• TDG converts G.T heteroduplexes to G.abasic sites, rendering DNA templates refractory to PCR amplification [27].
• The patients who were the most likely to benefit (ie, those with a greater improvement in pulmonary function and a significant reduction in the hospitalization rate) from TDG were those with more severe obstruction (ie, FEV(1), < 30% of predicted) [28].
• Routine urinalysis was performed and the urine analyzed for TDG using gas chromatography/mass spectrometry [29].
• TDG has been compared with hippuran and DTPA in normal subjects and the derived gamma camera renograms of both the whole kidney and parenchymal regions subjected to deconvolution analysis using the matrix algorithm [30].

References