Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJB0YIH)

• DOT Name: G/T mismatch-specific thymine DNA glycosylase (TDG)
• Synonyms: EC 3.2.2.29; Thymine-DNA glycosylase; hTDG
• Gene Name: TDG
• UniProt ID: TDG_HUMAN
• PDB ID: 1WYW; 2D07; 2RBA; 3UFJ; 3UO7; 3UOB; 4FNC; 4JGC; 4XEG; 4Z3A; 4Z47; 4Z7B; 4Z7Z; 5CYS; 5FF8; 5HF7; 5JXY; 5T2W; 6U15; 6U16; 6U17
• EC Number: 3.2.2.29
• Pfam ID: PF03167
• Sequence:
  MEAENAGSYSLQQAQAFYTFPFQQLMAEAPNMAVVNEQQMPEEVPAPAPAQEPVQEAPKG
  RKRKPRTTEPKQPVEPKKPVESKKSGKSAKSKEKQEKITDTFKVKRKVDRFNGVSEAELL
  TKTLPDILTFNLDIVIIGINPGLMAAYKGHHYPGPGNHFWKCLFMSGLSEVQLNHMDDHT
  LPGKYGIGFTNMVERTTPGSKDLSSKEFREGGRILVQKLQKYQPRIAVFNGKCIYEIFSK
  EVFGVKVKNLEFGLQPHKIPDTETLCYVMPSSSARCAQFPRAQDKVHYYIKLKDLRDQLK
  GIERNMDVQEVQYTFDLQLAQEDAKKMAVKEEKYDPGYEAAYGGAYGENPCSSEPCGFSS
  NGLIESVELRGESAFSGIPNGQWMTQSFTDQIPSFSNHCGTQEQEEESHA
• Function: DNA glycosylase that plays a key role in active DNA demethylation: specifically recognizes and binds 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) in the context of CpG sites and mediates their excision through base-excision repair (BER) to install an unmethylated cytosine. Cannot remove 5-hydroxymethylcytosine (5hmC). According to an alternative model, involved in DNA demethylation by mediating DNA glycolase activity toward 5-hydroxymethyluracil (5hmU) produced by deamination of 5hmC. Also involved in DNA repair by acting as a thymine-DNA glycosylase that mediates correction of G/T mispairs to G/C pairs: in the DNA of higher eukaryotes, hydrolytic deamination of 5-methylcytosine to thymine leads to the formation of G/T mismatches. Its role in the repair of canonical base damage is however minor compared to its role in DNA demethylation. It is capable of hydrolyzing the carbon-nitrogen bond between the sugar-phosphate backbone of the DNA and a mispaired thymine. In addition to the G/T, it can remove thymine also from C/T and T/T mispairs in the order G/T >> C/T > T/T. It has no detectable activity on apyrimidinic sites and does not catalyze the removal of thymine from A/T pairs or from single-stranded DNA. It can also remove uracil and 5-bromouracil from mispairs with guanine.
• KEGG Pathway: Base excision repair (hsa03410)
• Reactome Pathway:
  Cleavage of the damaged pyrimidine (R-HSA-110329)
  Displacement of DNA glycosylase by APEX1 (R-HSA-110357)
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)
  TET1,2,3 and TDG demethylate DNA (R-HSA-5221030)
  Recognition and association of DNA glycosylase with site containing an affected pyrimidine (R-HSA-110328)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	G/T mismatch-specific thymine DNA glycosylase (TDG) affects the response to substance of Doxorubicin.	[15]
Paclitaxel	DMLB81S	Approved	G/T mismatch-specific thymine DNA glycosylase (TDG) affects the response to substance of Paclitaxel.	[15]
Vinblastine	DM5TVS3	Approved	G/T mismatch-specific thymine DNA glycosylase (TDG) affects the response to substance of Vinblastine.	[15]

13 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of G/T mismatch-specific thymine DNA glycosylase (TDG).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of G/T mismatch-specific thymine DNA glycosylase (TDG).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of G/T mismatch-specific thymine DNA glycosylase (TDG).	[3]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of G/T mismatch-specific thymine DNA glycosylase (TDG).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of G/T mismatch-specific thymine DNA glycosylase (TDG).	[5]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of G/T mismatch-specific thymine DNA glycosylase (TDG).	[6]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of G/T mismatch-specific thymine DNA glycosylase (TDG).	[7]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of G/T mismatch-specific thymine DNA glycosylase (TDG).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of G/T mismatch-specific thymine DNA glycosylase (TDG).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of G/T mismatch-specific thymine DNA glycosylase (TDG).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of G/T mismatch-specific thymine DNA glycosylase (TDG).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of G/T mismatch-specific thymine DNA glycosylase (TDG).	[13]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of G/T mismatch-specific thymine DNA glycosylase (TDG).	[14]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of G/T mismatch-specific thymine DNA glycosylase (TDG).	[11]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [5] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [6] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [7] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [8] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [9] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [10] Benzo[a]pyrene-induced DNA damage associated with mutagenesis in primary human activated T lymphocytes. Biochem Pharmacol. 2017 Aug 1;137:113-124.
• [11] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [12] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [13] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [14] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [15] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.