TDG

Summary

TDG (thymine DNA glycosylase, HGNC:11700) is a protein-coding gene on chromosome 12q23.3, encoding G/T mismatch-specific thymine DNA glycosylase (Q13569). 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 cytosin….

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. This enzyme plays a central role in cellular defense against genetic mutation caused by the spontaneous deamination of 5-methylcytosine and cytosine. This gene may have a pseudogene in the p arm of chromosome 12.

Source: NCBI Gene 6996 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 66 total
• Druggable target: yes
• MANE Select transcript: NM_003211

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11700
Approved symbol	TDG
Name	thymine DNA glycosylase
Location	12q23.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000139372
Ensembl biotype	protein_coding
OMIM	601423
Entrez	6996

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 5 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000266775, ENST00000392872, ENST00000436021, ENST00000536395, ENST00000537100, ENST00000540956, ENST00000542926, ENST00000544060, ENST00000544861, ENST00000545698

RefSeq mRNA: 2 — MANE Select: NM_003211 NM_001363612, NM_003211

CCDS: CCDS86330, CCDS9095

Canonical transcript exons

ENST00000392872 — 10 exons

Exon	Start	End
ENSE00000937845	103983136	103983218
ENSE00001301388	103986948	103988874
ENSE00002234193	103965872	103966060
ENSE00003528205	103985603	103985728
ENSE00003564417	103979831	103980072
ENSE00003570570	103984749	103984920
ENSE00003588915	103980893	103980962
ENSE00003590498	103982799	103982934
ENSE00003645453	103976918	103977060
ENSE00003789112	103983295	103983389

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 98.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.7963 / max 302.3596, expressed in 1814 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
127723	23.5783	1810
127722	2.2997	1231
127721	1.9183	1061

Top tissues by expression

297 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	98.60	gold quality
esophagus squamous epithelium	UBERON:0006920	97.48	gold quality
visceral pleura	UBERON:0002401	97.36	gold quality
tibia	UBERON:0000979	97.34	gold quality
endothelial cell	CL:0000115	97.33	gold quality
squamous epithelium	UBERON:0006914	97.25	gold quality
epithelium of nasopharynx	UBERON:0001951	97.19	gold quality
gingival epithelium	UBERON:0001949	97.09	gold quality
tongue squamous epithelium	UBERON:0006919	96.87	gold quality
parietal pleura	UBERON:0002400	96.75	gold quality
pleura	UBERON:0000977	96.71	gold quality
amniotic fluid	UBERON:0000173	96.53	gold quality
germinal epithelium of ovary	UBERON:0001304	96.09	gold quality
cervix squamous epithelium	UBERON:0006922	95.90	gold quality
epithelium of esophagus	UBERON:0001976	95.61	gold quality
gingiva	UBERON:0001828	95.48	gold quality
hair follicle	UBERON:0002073	95.37	gold quality
endometrium epithelium	UBERON:0004811	95.30	gold quality
oviduct epithelium	UBERON:0004804	94.71	gold quality
palpebral conjunctiva	UBERON:0001812	94.63	gold quality
sperm	CL:0000019	94.46	gold quality
mucosa of sigmoid colon	UBERON:0004993	94.12	gold quality
oral cavity	UBERON:0000167	93.88	gold quality
penis	UBERON:0000989	93.69	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.49	gold quality
colonic mucosa	UBERON:0000317	93.28	gold quality
eye	UBERON:0000970	93.13	gold quality
pharyngeal mucosa	UBERON:0000355	92.87	gold quality
cartilage tissue	UBERON:0002418	92.55	gold quality
adrenal tissue	UBERON:0018303	92.53	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.21
E-CURD-114	yes	7.05

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DNMT3L, ESR1, ESR2, TP53

Literature-anchored findings (GeneRIF, showing 40)

• role in removing thymine produced by deamination of 5-methylcytosine and not removal of ethenocytosine (PMID:12493755)
• Xeroderma pigmentosum group C protein interacts physically and functionally with this enzyme (PMID:12505994)
• thymine-DNA glycosylase potentiates transcription of estrogen-regulated genes through direct interaction with estrogen receptor alpha (PMID:12874288)
• Polymorphisms in thymine DNA Glycosylase is associated with lung Neoplasms (PMID:15225156)
• unique range of each TDG activity corresponding to the three fractions indicates that human cells possibly express three distinct TDGs (PMID:15668625)
• Upon DNA interaction, TDG undergoes a dramatic conformational change, which involves its flexible N-terminal domain and accounts for its nonspecific DNA binding ability during base excision repair. (PMID:15823533)
• structure of the central region of human TDG conjugated to SUMO-1 at 2.1 A resolution (PMID:15959518)
• Results describe the crystal structure of the central region of thymine-DNA glycosylase conjugated to SUMO-3. (PMID:16626738)
• A novel missense variant A196G was found in familial colorectal cancer DNA suggesting a limited role for this gene in the devlopment of CRC. (PMID:17029639)
• TDG sumoylation promotes intramolecular interactions with amino- and carboxy-terminal SUMO-1 binding motifs that dramatically alter the biochemical properties and subcellular localization of TDG (PMID:17060459)
• The ability of human thymine-DNA glycosylase (TDG) to excise 8-(hydroxymethyl)-3,N(4)-ethenocytosine (8-hm-varepsilonC) and 3,N(4)-ethanocytosine (EC) was investigated and compared with varepsilonC, a known substrate for TDG. (PMID:17270163)
• analysis of 5-halogenated uracils in human thymine DNA glycosylase (PMID:17602166)
• Thymine DNA glycosylase activity is significantly stimulated by hHus1, hRad1, hRad9 separately, and by the 9-1-1 complex. (PMID:17855402)
• Expression of exogenous enzyme can functionally compensate for lower repair activities of damaged DNA in a myeloma cell line. (PMID:17965616)
• Studies lead to the characterization of a small structural domain in the TDG N-terminal region preceding the catalytic core and coinciding with the region of functional regulation of TDG’s activities. (PMID:18512959)
• A crystal structure of hTDG (catalytic domain, hTDG(cat)) in complex with abasic DNA, at 2.8 A resolution, is reported. (PMID:18587051)
• Apurinic/apyrimidinic endonuclease 1 actively stimulates thymine DNA glycosylase by disrupting the product complex (PMID:18805789)
• These observations suggest that TDG modulates the biological function of p53 and other members of the p53 family as a transcriptional coactivator. (PMID:18951877)
• There was a 1.198-fold increased micronucleus frequency for individuals carrying TDG 199Gly/Ser + Ser/Ser genotypes compared with those carrying Gly/Gly genotype (P < 0.05) for exposure to vinyl chloride. (PMID:19369898)
• excision of DNA-incorporated 5-FU by TDG generates persistent DNA strand breaks, delays S-phase progression, and activates DNA damage signaling (PMID:19402749)
• the TDG-NCoA-3 interaction is important for broad range activation of steroid hormone nuclear receptors (PMID:19652917)
• Role of two strictly conserved residues in nucleotide flipping and N-glycosylic bond cleavage by human thymine DNA glycosylase. (PMID:19880517)
• DNMT3L exerts a major effect on the transcriptional regulation of a specific target gene, such as thymine DNA glycosylase (PMID:20428781)
• Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: potential implications for active demethylation of CpG sites. (PMID:21862836)
• 5-carboxylcytosine is specifically recognized in the active site of thymine DNA glycosylase (PMID:22327402)
• We solved a crystal structure of TDG (catalytic domain) bound to a substrate analog and characterized active-site residues by mutagenesis, kinetics, and molecular dynamics simulations. (PMID:22573813)
• genetic variants in TDG, important not only in base excision repair but also in regulating the epigenome and gene expression, which may contribute to the non-melanoma skin cancer associated increase in overall cancer risk. (PMID:22581838)
• A structural study of catalysis by the thymine DNA glycosylase catalytic domain. (PMID:22962365)
• Human thymine-DNA glycosylase is able to excise 8oxoA in 8oxoA*T pairs. (PMID:23209024)
• Results imply that 5-carboxylcytosine (5caC) can adopt alternative conformations (either N157-interacting or N230-interacting) in the thymine DNA glycosylase active site to interact with either of the two asparagine side chain for 5caC excision. (PMID:23680598)
• TDG 3’untranslated region (UTR) contains two miR-29 binding sites; the miR-29 mimic decreases TDG mRNA by 40%, while miR-29 inhibitor increases TDG mRNA by 43.7% in human vascular smooth muscle cell cultures. (PMID:23820384)
• SIRT1 affects DNA repair through binding to thymine DNA glycosylase (TDG), stimulating TDG glycosylase activity, maintaining TDG in a hypoacetylated state, and regulating TDG expression (PMID:23952905)
• provide evidence for the existence of a functional ternary complex containing TDG, CBP and activated RARalpha (PMID:24394593)
• Thymine DNA glycosylase is a positive regulator of Wnt signaling in colorectal cancer (PMID:24532795)
• these findings provide insights into the in vivo dynamics of TDG SUMOylation and further clarify the TDG-RNF4 interaction. (PMID:24727457)
• TDG, as a new coactivator, promotes beta-catenin/TCFs transactivation and functionally cooperates with CBP in canonical Wnt signaling. (PMID:24748645)
• Whereas sumoylation substantially weakens TDG binding to DNA, TDG approximately SUMO-1 still binds relatively tightly to AP-DNA (Kd approximately 50 nM). (PMID:24753249)
• CRL4(Cdt2)-dependent degradation of TDG occurs in S phase because of the requirement for TDG to interact with chromatin-loaded PCNA, and this degradation is important for preventing toxicity from excess TDG. (PMID:24962565)
• Results show TARID binds to the TCF21 promoter and recruits GADD45A and TDG to direct base excision repair for demethylation. (PMID:25087872)
• these results suggest that individuals harboring the G199S in Thymine DNA glycosylase variant may have increased risk for developing cancer. (PMID:25375110)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tdg.1	ENSDARG00000013004
danio_rerio	tdg.2	ENSDARG00000086450
mus_musculus	Tdg	ENSMUSG00000034674
rattus_norvegicus	Tdg	ENSRNOG00000027124
drosophila_melanogaster	Tdg	FBGN0026869

Protein

Protein identifiers

G/T mismatch-specific thymine DNA glycosylase — Q13569 (reviewed: Q13569)

Alternative names: Thymine-DNA glycosylase

All UniProt accessions (6): Q13569, B4E127, F5H0I7, F5H539, G8JL98, H0YH18

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. Homodimer. Interacts with AICDA and GADD45A.

Subcellular location. Nucleus.

Post-translational modifications. Sumoylation on Lys-330 by either SUMO1 or SUMO2 induces dissociation of the product DNA.

Similarity. Belongs to the uracil-DNA glycosylase (UDG) superfamily. TDG/mug family.

RefSeq proteins (2): NP_001350541, NP_003202* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003310	TDG-like_euk	Family
IPR005122	Uracil-DNA_glycosylase-like	Domain
IPR015637	MUG/TDG	Family
IPR036895	Uracil-DNA_glycosylase-like_sf	Homologous_superfamily

Pfam: PF03167

Enzyme classification (BRENDA):

• EC 3.2.2.29 — thymine-DNA glycosylase (BRENDA: 7 organisms, 135 substrates, 15 inhibitors, 4 Km, 9 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
3,N4-ETHENOCYTOSINE-MISMATCHED DOUBLE-STRANDED D	—	1
THYMINE-MISMATCHED DOUBLE-STRANDED DNA	—	1
URACIL-MISMATCHED DOUBLE-STRANDED DNA	—	1
5-CHLOROURACIL-MISMATCHED DOUBLE-STRANDED DNA	—	0
5-FLUOROURACIL-MISMATCHED DOUBLE-STRANDED DNA	—	0

UniProt features (43 total): strand 11, helix 10, mutagenesis site 8, sequence variant 4, cross-link 4, sequence conflict 2, chain 1, region of interest 1, compositionally biased region 1, turn 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
4Z47	X-RAY DIFFRACTION	1.45
5HF7	X-RAY DIFFRACTION	1.54
6U17	X-RAY DIFFRACTION	1.55
6U16	X-RAY DIFFRACTION	1.6
5FF8	X-RAY DIFFRACTION	1.7
5JXY	X-RAY DIFFRACTION	1.71
4XEG	X-RAY DIFFRACTION	1.72
4Z3A	X-RAY DIFFRACTION	1.72
4Z7Z	X-RAY DIFFRACTION	1.83
4Z7B	X-RAY DIFFRACTION	2.02
1WYW	X-RAY DIFFRACTION	2.1
2D07	X-RAY DIFFRACTION	2.1
5T2W	X-RAY DIFFRACTION	2.2
6U15	X-RAY DIFFRACTION	2.4
5CYS	X-RAY DIFFRACTION	2.45
4FNC	X-RAY DIFFRACTION	2.49
4JGC	X-RAY DIFFRACTION	2.58
2RBA	X-RAY DIFFRACTION	2.79
3UFJ	X-RAY DIFFRACTION	2.97
3UO7	X-RAY DIFFRACTION	3
3UOB	X-RAY DIFFRACTION	3.01

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13569-F1	70.76	0.50

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (4): 103, 248, 330, 330

Mutagenesis-validated functional residues (8):

Position	Phenotype
140	loss of dna glycosylase activity but still able to bind dna.
145	increased dna glycosylase activity on g/t mispairs.
151	increased dna glycosylase activity on g/t mispairs.
191	reduced dna glycosylase activity on g/t and g/u mispairs.
197	reduced dna glycosylase activity on g/t mispairs.
281	restores the dna-binding ability of the sumoylated form.
310	restores the dna-binding ability of the sumoylated form.
315	restores the dna-binding ability of the sumoylated form.

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-110328	Recognition and association of DNA glycosylase with site containing an affected pyrimidine
R-HSA-110329	Cleavage of the damaged pyrimidine
R-HSA-110357	Displacement of DNA glycosylase by APEX1
R-HSA-3108214	SUMOylation of DNA damage response and repair proteins
R-HSA-5221030	TET1,2,3 and TDG demethylate DNA
R-HSA-212165	Epigenetic regulation of gene expression
R-HSA-2990846	SUMOylation
R-HSA-3108232	SUMO E3 ligases SUMOylate target proteins
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-73884	Base Excision Repair
R-HSA-73894	DNA Repair
R-HSA-73928	Depyrimidination
R-HSA-73929	Base-Excision Repair, AP Site Formation
R-HSA-73933	Resolution of Abasic Sites (AP sites)
R-HSA-74160	Gene expression (Transcription)

MSigDB gene sets: 226 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GEORGES_CELL_CYCLE_MIR192_TARGETS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, MODULE_16, KAUFFMANN_DNA_REPAIR_GENES, BROWNE_HCMV_INFECTION_12HR_UP, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, PUJANA_CHEK2_PCC_NETWORK, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_PYRIMIDINE_CONTAINING_COMPOUND_CATABOLIC_PROCESS, GTGCCTT_MIR506, MODULE_331, GOBP_PYRIMIDINE_NUCLEOTIDE_METABOLIC_PROCESS, GOBP_DNA_MODIFICATION

GO Biological Process (10): negative regulation of transcription by RNA polymerase II (GO:0000122), base-excision repair (GO:0006284), base-excision repair, AP site formation (GO:0006285), epigenetic regulation of gene expression (GO:0040029), depyrimidination (GO:0045008), regulation of embryonic development (GO:0045995), chromosomal 5-methylcytosine DNA demethylation, oxidation pathway (GO:0141167), DNA repair (GO:0006281), chromatin organization (GO:0006325), DNA damage response (GO:0006974)

GO Molecular Function (22): magnesium ion binding (GO:0000287), nucleic acid binding (GO:0003676), DNA binding (GO:0003677), damaged DNA binding (GO:0003684), double-stranded DNA binding (GO:0003690), transcription coregulator activity (GO:0003712), uracil DNA N-glycosylase activity (GO:0004844), protein kinase C binding (GO:0005080), ATP binding (GO:0005524), pyrimidine-specific mismatch base pair DNA N-glycosylase activity (GO:0008263), DNA N-glycosylase activity (GO:0019104), protein domain specific binding (GO:0019904), mismatched DNA binding (GO:0030983), sodium ion binding (GO:0031402), chloride ion binding (GO:0031404), SUMO binding (GO:0032183), G/U mismatch-specific uracil-DNA glycosylase activity (GO:0043739), DNA-binding transcription factor binding (GO:0140297), G/T mismatch-specific thymine-DNA glycosylase activity (GO:0141016), mismatch base pair DNA N-glycosylase activity (GO:0000700), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), plasma membrane (GO:0005886), PML body (GO:0016605)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Depyrimidination	2
Base Excision Repair	2
Resolution of Abasic Sites (AP sites)	1
SUMO E3 ligases SUMOylate target proteins	1
Epigenetic regulation of gene expression	1
Gene expression (Transcription)	1
Post-translational protein modification	1
SUMOylation	1
Metabolism of proteins	1
DNA Repair	1
Base-Excision Repair, AP Site Formation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	2
DNA binding	2
pyrimidine-specific mismatch base pair DNA N-glycosylase activity	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
DNA repair	1
base-excision repair	1
chromatin remodeling	1
regulation of gene expression	1
base-excision repair, AP site formation	1
DNA modification	1
pyrimidine deoxyribonucleotide catabolic process	1
embryo development	1
regulation of multicellular organismal development	1
positive regulation of gene expression, epigenetic	1
chromosomal 5-methylcytosine DNA demethylation pathway	1
DNA damage response	1
cellular component organization	1
cellular response to stress	1
metal ion binding	1
binding	1
nucleic acid binding	1
transcription regulator activity	1
deaminated base DNA N-glycosylase activity	1
protein kinase binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
mismatch base pair DNA N-glycosylase activity	1
hydrolase activity, hydrolyzing N-glycosyl compounds	1
catalytic activity, acting on DNA	1
protein binding	1
double-stranded DNA binding	1
alkali metal ion binding	1
anion binding	1
ubiquitin-like protein binding	1
uracil DNA N-glycosylase activity	1
transcription factor binding	1
DNA N-glycosylase activity	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1478 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TDG	GADD45A	P24522	983
TDG	SMUG1	Q53HV7	917
TDG	DNMT3A	Q9Y6K1	909
TDG	UNG	P13051	906
TDG	MBD4	O95243	897
TDG	TET1	Q8NFU7	886
TDG	DNMT3B	Q9UBC3	865
TDG	EP300	Q09472	849
TDG	SUMO1	P55856	828
TDG	MUTYH	Q9UIF7	815
TDG	OGG1	P78554	811
TDG	TET3	O43151	809
TDG	APEX1	P27695	786
TDG	DNMT1	P26358	785
TDG	NTHL1	P78549	775

IntAct

78 interactions, top by confidence:

A	B	Type	Score
TDG	SUMO1	psi-mi:“MI:0407”(direct interaction)	0.670
SUMO1	TDG	psi-mi:“MI:0915”(physical association)	0.670
TDG	NCOA1	psi-mi:“MI:0915”(physical association)	0.580
NCOA1	TDG	psi-mi:“MI:0915”(physical association)	0.580
NCOA1	TDG	psi-mi:“MI:0914”(association)	0.580
TDG	NCOA1	psi-mi:“MI:0914”(association)	0.580
TDG	AICDA	psi-mi:“MI:0915”(physical association)	0.580
AICDA	TDG	psi-mi:“MI:0915”(physical association)	0.580
TDG	SUMO2	psi-mi:“MI:0407”(direct interaction)	0.560
TDG	APBB2	psi-mi:“MI:0915”(physical association)	0.560
TDG		psi-mi:“MI:0915”(physical association)	0.560
GRN	TDG	psi-mi:“MI:0915”(physical association)	0.560
TDG	HSPB1	psi-mi:“MI:0915”(physical association)	0.560
TDG	NEFL	psi-mi:“MI:0915”(physical association)	0.560
TDG	PMP22	psi-mi:“MI:0915”(physical association)	0.560
TDG	PRPS1	psi-mi:“MI:0915”(physical association)	0.560
TDG	TTR	psi-mi:“MI:0915”(physical association)	0.560
TDG	WFS1	psi-mi:“MI:0915”(physical association)	0.560
KIF1B	TDG	psi-mi:“MI:0915”(physical association)	0.560
RNF11	TDG	psi-mi:“MI:0915”(physical association)	0.560
SNCA	TDG	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (115): TCF4 (Affinity Capture-Western), CREBBP (Affinity Capture-Western), TDG (Affinity Capture-RNA), RARA (Affinity Capture-Western), CREBBP (Affinity Capture-Western), TDG (Biochemical Activity), TDG (Reconstituted Complex), TDG (Reconstituted Complex), TDG (Two-hybrid), TDG (Affinity Capture-Western), TDG (Two-hybrid), XPC (Two-hybrid), XPC (Reconstituted Complex), TDG (Two-hybrid), TDG (Two-hybrid)

ESM2 similar proteins: A0A0R4IXF6, E1B7L7, E7F7X0, E9QA62, F7BJB9, O60502, P03373, P35398, P35611, P35612, P51448, P56581, P59997, P97496, P97874, Q05764, Q0VBD2, Q13569, Q1LUC3, Q3YBR2, Q498E7, Q5R5V7, Q5RA10, Q5RHD1, Q5RIX9, Q63028, Q6DFJ8, Q6EU10, Q6INA9, Q6PDG5, Q7L590, Q7T293, Q7TNY6, Q80TZ3, Q80U87, Q8BMP6, Q8C5W4, Q8VIJ5, Q92830, Q92831

Diamond homologs: A1AFY9, A4WEK3, A6TE50, A7MJU3, A7ZRV0, A8A4M5, A8APW0, A8GJV5, A9MPV1, A9N5Z1, B1IRP8, B1LF61, B1XG73, B2U1S3, B4T682, B4TI63, B4TVU6, B5BG24, B5F6A8, B5FHU7, B5QZ48, B5REH0, B5XU18, B5YRA8, B6I441, B7LH04, B7LQE3, B7LZL8, B7MB04, B7N0L8, B7ND57, B7NJT2, C0PYY5, C4ZQY5, C6DKG5, P0A9H1, P0A9H2, P43343, P56581, Q0T0J4

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
DTL	“down-regulates quantity by destabilization”	TDG	binding
Cullin4-RBX1-DDB1	“down-regulates quantity by destabilization”	TDG	polyubiquitination
TDG	up-regulates	Base-excision_repair

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 31 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Cytokine Signaling in Immune system	5	7.8×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

66 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	46
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1308 predictions. Top by Δscore:

Variant	Effect	Δscore
12:103976916:A:AG	acceptor_gain	1.0000
12:103976917:G:GA	acceptor_gain	1.0000
12:103976917:GCT:G	acceptor_gain	1.0000
12:103977048:G:GT	donor_gain	1.0000
12:103977056:GCAAG:G	donor_loss	1.0000
12:103977057:CAAGG:C	donor_loss	1.0000
12:103977058:AAG:A	donor_loss	1.0000
12:103977059:AGGT:A	donor_loss	1.0000
12:103977060:GG:G	donor_loss	1.0000
12:103977061:G:C	donor_loss	1.0000
12:103977062:T:A	donor_loss	1.0000
12:103979827:TCA:T	acceptor_loss	1.0000
12:103979828:CA:C	acceptor_loss	1.0000
12:103979829:A:AG	acceptor_gain	1.0000
12:103979829:AGAG:A	acceptor_gain	1.0000
12:103979830:G:GG	acceptor_gain	1.0000
12:103979830:GA:G	acceptor_gain	1.0000
12:103979830:GAGG:G	acceptor_gain	1.0000
12:103980068:TCATT:T	donor_gain	1.0000
12:103980071:TT:T	donor_gain	1.0000
12:103980073:G:GG	donor_gain	1.0000
12:103980100:A:AG	donor_gain	1.0000
12:103980100:A:G	donor_gain	1.0000
12:103980105:T:TA	donor_gain	1.0000
12:103980106:A:AA	donor_gain	1.0000
12:103980887:TTATA:T	acceptor_loss	1.0000
12:103980888:TATA:T	acceptor_loss	1.0000
12:103980889:ATAG:A	acceptor_loss	1.0000
12:103980890:T:G	acceptor_gain	1.0000
12:103980890:TAGAT:T	acceptor_loss	1.0000

AlphaMissense

2716 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:103979995:T:C	F111L	1.000
12:103979996:T:C	F111S	1.000
12:103979997:T:A	F111L	1.000
12:103979997:T:G	F111L	1.000
12:103980035:T:A	L124H	1.000
12:103980040:G:C	D126H	1.000
12:103980047:T:C	L128S	1.000
12:103980068:T:A	V135D	1.000
12:103980896:G:C	G138R	1.000
12:103980896:G:T	G138C	1.000
12:103980897:G:A	G138D	1.000
12:103980897:G:T	G138V	1.000
12:103980900:T:A	I139K	1.000
12:103980900:T:C	I139T	1.000
12:103980900:T:G	I139R	1.000
12:103980902:A:G	N140D	1.000
12:103980904:C:A	N140K	1.000
12:103980904:C:G	N140K	1.000
12:103980905:C:T	P141S	1.000
12:103980906:C:A	P141Q	1.000
12:103980908:G:A	G142R	1.000
12:103980908:G:C	G142R	1.000
12:103980909:G:A	G142E	1.000
12:103980918:C:A	A145D	1.000
12:103980921:C:A	A146D	1.000
12:103980932:C:G	H150D	1.000
12:103980935:C:G	H151D	1.000
12:103980937:T:A	H151Q	1.000
12:103980937:T:G	H151Q	1.000
12:103980938:T:C	Y152H	1.000

dbSNP variants (sampled 300 via entrez): RS1000065794 (12:103971338 C>T), RS1000067695 (12:103986129 G>A), RS1000077395 (12:103971094 T>C), RS1000321779 (12:103976481 A>C), RS1000334263 (12:103982708 T>A), RS1000377654 (12:103965028 G>A,T), RS1000386461 (12:103982475 T>C), RS1000610279 (12:103975394 A>G), RS1000718329 (12:103981305 G>A), RS1000868475 (12:103989044 T>C), RS1000935131 (12:103966489 C>T), RS1001021085 (12:103973352 C>T), RS1001062681 (12:103975114 T>C), RS1001366789 (12:103979608 G>A,T), RS1001388623 (12:103984156 A>G)

Disease associations

OMIM: gene MIM:601423 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): hereditary breast ovarian cancer syndrome (MONDO:0003582)

Orphanet (1): Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST005162_4	Glucagon levels in response to oral glucose tolerance test (fasting)	4.000000e-06
GCST009391_1344	Metabolite levels	7.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004307	glucose tolerance test
EFO:0008463	glucagon measurement
EFO:0010362	lysophosphatidylcholine 20:3 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465279 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

48 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases reaction, affects cotreatment, increases abundance, increases expression, decreases expression	3
Hydrogen Peroxide	affects expression, affects cotreatment, increases expression	3
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Smoke	decreases expression, increases abundance	2
Valproic Acid	decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
uranyl acetate	affects expression	1
bisphenol A	affects expression	1
beta-lapachone	increases expression, decreases expression	1
3,N(4)-ethenocytosine	increases metabolic processing	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
ochratoxin A	decreases acetylation, decreases expression	1
cupric oxide	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
JP8 aviation fuel	increases expression	1
CPG-oligonucleotide	increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Acetaminophen	decreases expression	1
Acrolein	increases oxidation, increases abundance, affects cotreatment	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Ascorbic Acid	decreases expression, decreases reaction	1
Benzo(a)pyrene	increases expression	1
Doxorubicin	affects response to substance	1

ChEMBL screening assays

9 unique, capped per target: 8 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5393571	Binding	Inhibition of TDG (unknown origin) mismatch repair activity using double-stranded DNA probe T1-T2 as substrate preincubated for 30 mins followed by substrate addition and measured after 30 mins by fluorescence based assay	Compounds inhibiting tdg activity
CHEMBL5665452	Functional	Inhibition of TDG by quantifying inhibition of TDG-mediated cleavage and dissociation of quenched duplex DNA oligonucleotides, measured as fluorescence at 594 nm. To generate a functional strand incision and increase turn-over this assay is	Enzyme Inhibitor Single Concentration assay results for EUbOPEN Chemogenomics Library

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_TR82	HAP1 TDG (-) 1	Cancer cell line	Male
CVCL_XU12	HAP1 TDG (-) 2	Cancer cell line	Male
CVCL_XU13	HAP1 TDG (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

51 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00673335	PHASE3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	PHASE3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	PHASE3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00253539	PHASE2	COMPLETED	Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer
NCT00305695	PHASE2	COMPLETED	Zoledronate or Observation in Maintaining Bone Mineral Density in Patients Who Are Undergoing Surgery to Remove Both Ovaries
NCT00321633	PHASE2	COMPLETED	Carboplatin or Docetaxel in Treating Women With Metastatic Genetic Breast Cancer
NCT01333748	PHASE2	COMPLETED	Search Allelic Imbalance of Expression of BRCA Genes in Hereditary Risk of Breast and/or Ovarian Cancer
NCT01367639	PHASE2	COMPLETED	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00535119	PHASE1	COMPLETED	Veliparib, Carboplatin, and Paclitaxel in Treating Patients With Advanced Solid Cancer
NCT00892736	PHASE1	COMPLETED	Veliparib in Treating Patients With Malignant Solid Tumors That Do Not Respond to Previous Therapy
NCT03832985	EARLY_PHASE1	COMPLETED	Pediatric Reporting of Adult-Onset Genomic Results
NCT00005095	Not specified	RECRUITING	Specimen and Data Study for Ovarian Cancer Early Detection and Prevention
NCT00609505	Not specified	COMPLETED	Telemedicine vs. Face-to-Face Cancer Genetic Counseling
NCT01273909	Not specified	UNKNOWN	Outcomes After Perforator Flap Reconstruction for Breast Reconstruction and/or Lymphedema Treatment
NCT01445275	Not specified	WITHDRAWN	Cost of Cancer Risk Management in Women at Elevated Genetic Risk for Ovarian Cancer Who Participated on GOG-0199
NCT01608074	Not specified	ACTIVE_NOT_RECRUITING	Radical Fimbriectomy for Young BRCA Mutation Carriers
NCT02087592	Not specified	COMPLETED	Feasibility of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02302742	Not specified	RECRUITING	Triple Negative Breast Cancer and Germline Hereditary Breast and Ovarian Cancer Mutation Carrier Registry
NCT02324062	Not specified	COMPLETED	Cancer Genetics Hereditary Cancer Panel Testing
NCT02516540	Not specified	UNKNOWN	Efficacy of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02653105	Not specified	ACTIVE_NOT_RECRUITING	Women at Risk of Breast Cancer and OLFM4
NCT02705924	Not specified	TERMINATED	Impact of a Psychoeducational Intervention on Expectations and Coping in Young Women Exposed to a High HBOC Risk
NCT02760849	Not specified	ACTIVE_NOT_RECRUITING	Surgery in Preventing Ovarian Cancer in Patients With Genetic Mutations
NCT02786147	Not specified	COMPLETED	Identification and Referral of Women at Risk for Hereditary Breast/Ovarian Cancer
NCT02956681	Not specified	COMPLETED	Statewide Communication to Reach Diverse Low Income Women
NCT03015376	Not specified	UNKNOWN	Inherited Susceptible Genes Among Epithelial Ovarian Cancer
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03075540	Not specified	COMPLETED	Enhancing At-risk Latina Women’s Use of Genetic Counseling for Hereditary Breast and Ovarian Cancer
NCT03124212	Not specified	RECRUITING	Cascade Genetic Testing for Hereditary Breast/Ovarian Cancer and Lynch Syndrome in Switzerland
NCT03246841	Not specified	ACTIVE_NOT_RECRUITING	Investigation of Tumour Spectrum of Germline Mutations in Breast and Ovarian Cancer Genes.
NCT03294343	Not specified	UNKNOWN	Risk-Reducing Surgeries for Hereditary Ovarian Cancer
NCT03421327	Not specified	COMPLETED	Genetic Risk: Whether, When, and How to Tell Adolescents
NCT03510689	Not specified	COMPLETED	Genetics and Heart Health After Cancer Therapy
NCT03511690	Not specified	COMPLETED	Testing an Intelligent Tutoring System to Enhance Genetic Risk Assessment
NCT03784859	Not specified	COMPLETED	Tissue Expansion in Breast Reconstruction Without Drains
NCT03979612	Not specified	UNKNOWN	Evaluation of the Adhesion to the GENEPY Network
NCT04197856	Not specified	ACTIVE_NOT_RECRUITING	Direct Information to At-risk Relatives
NCT04407611	Not specified	COMPLETED	Scalable Communication Modalities for Returning Genetic Research Results
NCT04508764	Not specified	TERMINATED	Implementation of the Families Accelerating Cascade Testing Toolkit (FACTT) for Hereditary Breast and Ovarian Cancer and Lynch Syndrome