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Information on EC 3.2.2.29 - thymine-DNA glycosylase and Organism(s) Homo sapiens and UniProt Accession Q13569
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3.2.2.29 thymine-DNA glycosylaseIUBMB Comments
Thymine-DNA glycosylase is part of the DNA-repair machinery. Thymine removal is fastest when it is from a G/T mismatch with a 5'-flanking C/G pair. The glycosylase removes uracil from G/U, C/U, and T/U base pairs faster than it removes thymine from G/T .
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Word Map
- 3.2.2.29
-
demethylation
- 5-methylcytosine
- cytosine
-
deamination
- glycosylases
- 5-carboxylcytosine
- mispairs
- 5-formylcytosine
-
5-hydroxymethylcytosine
-
ten-eleven
-
excises
-
uracil-dna
-
abasic
-
methyl-cpg
- 3,n4-ethenocytosine
-
tdg-mediated
- 5-hydroxymethyluracil
- sumo-1
-
base-excision
-
methyl-cpg-binding
- medicine
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Archaea, Eukaryota
The expected taxonomic range for this enzyme is: Archaea, Eukaryota
Reaction Schemes
Hydrolyses mismatched double-stranded DNA and polynucleotides, releasing free thymine.
Synonyms
thymine dna glycosylase, thymine-dna glycosylase, mismatch-specific thymine-dna glycosylase, pa-mig, g/t glycosylase, thymine dna-glycosylase, uracil/thymine dna glycosylase, mismatch-specific thymine-dna n-glycosylase, t:g mismatch-specific thymidine-dna glycosylase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
TDG
-
thymine DNA glycosylase
-
TDG
-
-
thymine DNA glycosylase
-
-
additional information
additional information
the enzyme belongs to the uracil-DNA glycosylase family
additional information
the enzyme is a member of the uracil DNA glycosylase, UDG, superfamily
SYSTEMATIC NAME
IUBMB Comments
thymine-DNA deoxyribohydrolase (thymine-releasing)
Thymine-DNA glycosylase is part of the DNA-repair machinery. Thymine removal is fastest when it is from a G/T mismatch with a 5'-flanking C/G pair. The glycosylase removes uracil from G/U, C/U, and T/U base pairs faster than it removes thymine from G/T [3].
CAS REGISTRY NUMBER
COMMENTARY
149565-68-4
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
3,N4-ethenocytosine-mismatched double-stranded DNA + H2O
3,N4-ethenocytosine + double-stranded DNA with abasic site
5-bromocytosine-mismatched double-stranded DNA + H2O
5-bromouracil + double-stranded DNA with abasic site
hTDG readily excises cytosine analogues with improved leaving ability, including 5-fluorocytosine, 5-bromocytosine, and 5-hydroxycytosine, indicating that cytosine has access to the active site. hTDG specificity depends on N-glycosidic bond stability, and the discrimination against cytosine is due largely to its very poor leaving ability rather than its exclusion from the active site
-
-
?
5-bromouracil-mismatched double-stranded DNA + H2O
5-bromouracil + double-stranded DNA with abasic site
5-carboxylcytosine mismatched double-stranded DNA + H2O
5-carboxylcytosine + double-stranded DNA with abasic site
-
-
-
?
5-carboxylcytosine-mismatched double-stranded DNA + H2O
5-carboxylcytosine + double-stranded DNA with abasic site
5-chlorouracil-mismatched double-stranded DNA + H2O
5-chlorouracil + double-stranded DNA with abasic site
5-fluorocytosine-mismatched double-stranded DNA + H2O
5-fluorocytosine + double-stranded DNA with abasic site
hTDG readily excises cytosine analogues with improved leaving ability, including 5-fluorocytosine, 5-bromocytosine, and 5-hydroxycytosine, indicating that cytosine has access to the active site. hTDG specificity depends on N-glycosidic bond stability, and the discrimination against cytosine is due largely to its very poor leaving ability rather than its exclusion from the active site
-
-
?
5-fluorouracil-mismatched double-stranded DNA + H2O
5-fluorouracil + double-stranded DNA with abasic site
5-formylcytosine mismatched double-stranded DNA + H2O
5-formylcytosine + double-stranded DNA with abasic site
-
-
-
?
5-formylcytosine-mismatched double-stranded DNA + H2O
5-formylcytosine + double-stranded DNA with abasic site
5-hydroxcytosine-mismatched double-stranded DNA + H2O
5-hydroxycytosine + double-stranded DNA with abasic site
hTDG readily excises cytosine analogues with improved leaving ability, including 5-fluorocytosine, 5-bromocytosine, and 5-hydroxycytosine, indicating that cytosine has access to the active site. hTDG specificity depends on N-glycosidic bond stability, and the discrimination against cytosine is due largely to its very poor leaving ability rather than its exclusion from the active site
-
-
?
5-hydroxymethyluracil-mismatched double-stranded DNA + H2O
5-hydroxymethyluracil + double-stranded DNA with abasic site
5-hydroxymethyluridine-mismatched double-stranded DNA + H2O
5-hydroxymethyluridine + double-stranded DNA with abasic site
-
-
-
?
5-hydroxyuracil-mismatched double-stranded DNA + H2O
5-hydroxyuracil + double-stranded DNA with abasic site
removes 5-hydroxyuracil from G/5-hydroxyuracil mismatches
-
-
?
5-methylcytosine-mismatched double-stranded DNA + H2O
5-methylcytosine + double-stranded DNA with abasic site
paired with guanine
-
-
?
8-(hydroxymethyl)-3,N4-ethenocytosine-mismatched double-stranded DNA + H2O
8-(hydroxymethyl)-3,N4-ethenocytosine + double-stranded DNA with abasic site
TDG is able to excise the 8-(hydroxymethyl)-3,N4-ethenocytosine from DNA. TDG activity displays a marked preference of guanine opposite to 8-(hydroxymethyl)-3,N4-ethenocytosine over any other bases. TDG does not show any detectable activity toward 3,N4-ethanocytosine when placed in various neighboring sequences, including the 5'-CpG site
-
-
?
cytosine-mismatched double-stranded DNA + H2O
cytosine + double-stranded DNA with abasic site
paired with guanine
-
-
?
double-stranded DNA + H2O
?
thymine-DNA glycosylase has a strong sequence preference for CpG sites in the excision of both thymine and ethenocytosine. This suggests a main role of thymine-DNA glycosylase in vivo is the removal of thymine produced by deamination of 5-methylcytosine at CpG sites
-
-
?
thymine glycol -mismatched double-stranded DNA + H2O
thymine glycol + double-stranded DNA with abasic site
thymine glycol from G/thymine glycol mismatches
-
-
?
thymine-guanine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
uridine-mismatched double-stranded DNA + H2O
uridine + double-stranded DNA with abasic site
-
-
-
?
5-bromouracil-mismatched double-stranded DNA + H2O
5-bromouracil + double-stranded DNA with abasic site
-
in addition to uracil and thymine, the protein can also remove 5-bromouracil from mispairs with guanine
-
-
?
thymine glycol-mismatched double-stranded DNA + H2O
thymine glycol + double-stranded DNA with abasic site
-
oligonucleotides with thymine glycol incorporated into different sequence contexts and paired with adenine or guanine. TDG and methyl-CpG-binding protein 4 can remove thymine glycol when present opposite guanine but not when paired with adenine. The efficiency of these enzymes for removal of thymine glycol is about half of that for removal of thymine in the same sequence context. The two proteins may have evolved to act specifically on DNA mismatches produced by deamination and by oxidation-coupled deamination of 5-methylcytosine. This repair pathway contributes to mutation avoidance at methylated CpG dinucleotides
-
-
?
thymine-guanine mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
3,N4-ethenocytosine-mismatched double-stranded DNA + H2O
3,N4-ethenocytosine + double-stranded DNA with abasic site
-
-
-
?
3,N4-ethenocytosine-mismatched double-stranded DNA + H2O
3,N4-ethenocytosine + double-stranded DNA with abasic site
3,N4-ethenocytosine is recognized and efficiently excised by hTDG. The enzyme may be responsible for the repair of this mutagenic lesion in vivo and be important contributors to genetic stability
-
-
?
3,N4-ethenocytosine-mismatched double-stranded DNA + H2O
3,N4-ethenocytosine + double-stranded DNA with abasic site
3,N4-ethenocytosine is recognized and efficiently excised from the 3,N4-ethenocytosine/G duplex oligonucleotide, when this residue is situated opposite to G. 26.5% of the activity measured with 3,N4-ethenocytosine mismatches is observed with 3,N4-ethenocytosine/A mismatches, 71% with 3,N4-ethenocytosine/A mismatches
-
-
?
3,N4-ethenocytosine-mismatched double-stranded DNA + H2O
3,N4-ethenocytosine + double-stranded DNA with abasic site
ethenocytosine base-paired with guanine within a CpG site (i.e. CpG-ethenocytosine-DNA) is by far the best substrate. The next best substrates are DNA duplexes containing TpG/ethenocytosine, GpG/ethenocytosine, and CpG/T. The worst substrates are DNA duplexes containing ApG/ethenocytosine and TpG/T. DNA containing ethenocytosine is bound much more tightly than DNA containing a G/T mismatch
-
-
?
3,N4-ethenocytosine-mismatched double-stranded DNA + H2O
3,N4-ethenocytosine + double-stranded DNA with abasic site
removes 3,N4-ethenocytosine from G/3,N4-ethenocytosine and A/3,N4-ethenocytosine mismatches
-
-
?
5-bromouracil-mismatched double-stranded DNA + H2O
5-bromouracil + double-stranded DNA with abasic site
potential role played by human TDG in the cytotoxic effects of 5-chlorouracil and 5-bromouracil incorporation into DNA, which can occur under inflammatory conditions
-
-
?
5-bromouracil-mismatched double-stranded DNA + H2O
5-bromouracil + double-stranded DNA with abasic site
paired with guanine
-
-
?
5-bromouracil-mismatched double-stranded DNA + H2O
5-bromouracil + double-stranded DNA with abasic site
removes 5-bromouracil from G/5-bromouracil mismatches
-
-
?
5-carboxylcytosine-mismatched double-stranded DNA + H2O
5-carboxylcytosine + double-stranded DNA with abasic site
-
-
-
?
5-carboxylcytosine-mismatched double-stranded DNA + H2O
5-carboxylcytosine + double-stranded DNA with abasic site
-
-
-
-
?
5-carboxylcytosine-mismatched double-stranded DNA + H2O
5-carboxylcytosine + double-stranded DNA with abasic site
-
-
-
?
5-chlorouracil-mismatched double-stranded DNA + H2O
5-chlorouracil + double-stranded DNA with abasic site
potential role played by human TDG in the cytotoxic effects of 5-chlorouracil and 5-bromouracil incorporation into DNA, which can occur under inflammatory conditions
-
-
?
5-chlorouracil-mismatched double-stranded DNA + H2O
5-chlorouracil + double-stranded DNA with abasic site
hTDG removes 5-chlorouracil 572fold faster than thymine
-
-
?
5-chlorouracil-mismatched double-stranded DNA + H2O
5-chlorouracil + double-stranded DNA with abasic site
removes a variety of damaged bases (X) with a preference for lesions in a CpG/X context. The maximal activity for G/X substrates depends significantly on the 5' base pair. The maximal activity decreases by 6fold, 11fold, and 82fold for TpG/5-chlorouracil, GpG/5-chlorouracil, and ApG/5-chlorouracil, respectively, as compared with CpG/5-chlorouracil. Human TDG activity is reduced 102.3104.3fold for A/X relative to G/X pairs and reduced further for A/X pairs with a 5' pair other than C/G. The effect of altering the 5' pair and/or the opposing base (G/X versus A/X) is greater for substrates that are larger (bromodeoxyuridine, dT) or have a more stable N-glycosidic bond (such as dT). The largest CpG context effects are observed for the excision of thymine
-
-
?
5-fluorouracil-mismatched double-stranded DNA + H2O
5-fluorouracil + double-stranded DNA with abasic site
hTDG removes 5-fluorouracil 78fold faster than uracil
-
-
?
5-fluorouracil-mismatched double-stranded DNA + H2O
5-fluorouracil + double-stranded DNA with abasic site
paired with guanine
-
-
?
5-fluorouracil-mismatched double-stranded DNA + H2O
5-fluorouracil + double-stranded DNA with abasic site
removes 5-fluorouracil from G/5-fluorouracil and A/5-fluorouracil mismatches
-
-
?
5-fluorouracil-mismatched double-stranded DNA + H2O
5-fluorouracil + double-stranded DNA with abasic site
the activity for G/5-fluorouracil, G/5-chlorouracil, and G/5-bromouracil, with any 5'-flanking pair, meets and in most cases significantly exceeds the CpG/T activity. Human TDG activity is reduced 102.3104.3fold for A/X relative to G/X pairs and reduced further for A/X pairs with a 5' pair other than C/G. The effect of altering the 5' pair and/or the opposing base (G/X versus A/X) is greater for substrates that are larger (bromodeoxyuridine, dT) or have a more stable N-glycosidic bond (such as dT). The largest CpG context effects are observed for the excision of thymine
-
-
?
5-formylcytosine-mismatched double-stranded DNA + H2O
5-formylcytosine + double-stranded DNA with abasic site
-
-
-
?
5-formylcytosine-mismatched double-stranded DNA + H2O
5-formylcytosine + double-stranded DNA with abasic site
-
-
-
-
?
5-formylcytosine-mismatched double-stranded DNA + H2O
5-formylcytosine + double-stranded DNA with abasic site
-
-
-
?
5-hydroxymethyluracil-mismatched double-stranded DNA + H2O
5-hydroxymethyluracil + double-stranded DNA with abasic site
-
-
-
?
5-hydroxymethyluracil-mismatched double-stranded DNA + H2O
5-hydroxymethyluracil + double-stranded DNA with abasic site
paired with guanine
-
-
?
5-hydroxymethyluracil-mismatched double-stranded DNA + H2O
5-hydroxymethyluracil + double-stranded DNA with abasic site
removes 5-hydroxymethyluracil from G/5-hydroxymethyluracil mismatches
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
about 23% of mutations in hereditary human diseases and 24% of mutations in p53 in human cancers are G to A transitions at sites of cytosine methylation suggesting that these sites are either foci for DNA damage, or foci for damage that is poorly repaired. Thymine produced at these sites by the hydrolytic deamination of 5-methylcytosine is removed by thymine-DNA glycosylase. Thymine-DNA glycosylase also removes 3,N4-ethenocytosine and uracil from DNA. The action of this enzyme is limited by its very low kcat and by tight binding to the apurinic site produced when the thymine is removed. These properties of the enzyme suggest that the inefficiency of the base excision repair pathway that it initiates may be the underlying cause of the prevalence of these mutations
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
the enzyme initiates the repair process by excising the mispaired thymine from the heteroduplex to generate an apyrimidinic site
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
the human enzyme excises thymine and uracil from G-T and G-U mismatches, respectively, and is therefore proposed to play a central role in the cellular defense against genetic mutation through spontaneous deamination of 5-methylcytosine and cytosine
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
45-bp DNA heteroduplexes that bear single G/T, O6-methyguanine, 2,6-diaminopurine/T, 2-amino-6-(methylamino)-purine/T, 2-aminopurine/T, and G/O4-methylthymine mispairs. The bases 5' to the poorly matched G are altered in selected G/T substrates to yield mispairs in four different contexts, ApG, CpG, GpG, and TpG. The recombinant thymine glycosylase is incubated with the 45-bp DNA substrates, each labeled at the 5'-terminus of the strand containing the mismatched T. The rate of incision is greatest with DNA containing the G/T mispair followed by the DNA containing the O6-methylguanine/T mispair and the DNA with the 2-amino-6-(methylamino)purine/T mispair. The extent of reaction is 90%, 40%, and 20% respectively. DNA substrates containing 2,6-diaminopurine/T, 2-aminopurine/T, and G/O4-methylthymine mispairs are not incised. The amount of incision of the 45-bp DNA substrates containing G/T mispairs in the CpG context is 3-12fold greater than in the TpG, GpG, and ApG contexts
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
cleaves thymine from mutagenic G/T mispairs. Recognizes many additional lesions, and has a strong preference for nucleobases paired with guanine rather than adenine. hTDG avoids cytosine, despite the million-fold excess of normal G/C pairs over G/T mispairs
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
each molecule of thymine DNA glycosylase removes only one molecule of thymine from DNA containing a G/T mismatch because it binds tightly to the apurinic DNA site left after removal of thymine. The 5'-flanking base pair to G/T mismatches influences the rate of removal of thymine. Thymine DNA glycosylase can also remove thymine from mismatches with S6-methylthioguanine, but, unlike G/T mismatches, a 5'-C-G does not have a striking effect on the rate. Thymine removal is fastest when it is from a G/T mismatch with a 5'-flanking C/G pair, suggesting that the rapid reaction of this substrate involves contacts between the enzyme and oxygen 6 or the N-1 hydrogen of the mismatched guanine as well as the 5'-flanking C/G pair
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
ethenocytosine base-paired with guanine within a CpG site (i.e. CpG-ethenocytosine-DNA) is by far the best substrate. The next best substrates are DNA duplexes containing TpG/ethenocytosine, GpG/ethenocytosine, and CpG/T. The worst substrates are DNA duplexes containing ApG/ethenocytosine and TpG/T. DNA containing ethenocytosine is bound much more tightly than DNA containing a G/T mismatch
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
excision of thymine from T/G mismatches
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
paired with guanine
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
removes thymine from G/T mismatches
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
the enzyme is capable for hydrolyzing the carbon-nitrogen bond between the sugar-phosphate backbone of the DNA and a mispaired thymine. In addition to G/T, the enzyme can remove thymine also from C/T and T/T mispairs in the order of decreasing efficiency: G/T, C/T, T/T. It has no detectable endonucleolytic activity on apyrimidinic sites and does not catalyze the removal of thymine from A/T pairs or from single-stranded DNA
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
the recombinant enzyme shows a significant preference for G/T mispairs in a CpG context. The enzyme is also capable of processing mismatches between thymine and 6-O-methylguanine, whereby it generates an apyrimidinic site opposite the modified guanine. TDG preferentially addresses 6-O-methyl G/T mispairs when the neighboring base 5' to the 6-O-methyl G is a C rather than a G. TDG is the only enzyme present in the HeLa nuclear extracts capable of processing G/T mispairs in oligonucleotide substrate
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
thymine DNA glycosylase excises thymine from G/T mispairs. Human TDG activity is reduced 102.3104.3fold for A/X relative to G/X pairs and reduced further for A/X pairs with a 5' pair other than C/G. The effect of altering the 5' pair and/or the opposing base (G/X versus A/X) is greater for substrates that are larger (bromodeoxyuridine, dT) or have a more stable N-glycosidic bond (such as dT). The largest CpG context effects are observed for the excision of thymine
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
thymine-DNA glycosylase is more active on mismatches containing uracil than on mismatches containing thymine
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
-
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
-
-
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
-
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
the human enzyme excises thymine and uracil from G-T and G-U mismatches, respectively, and is therefore proposed to play a central role in the cellular defense against genetic mutation through spontaneous deamination of 5-methylcytosine and cytosine
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
thymine DNA glycosylase may play a backup role to the more efficient general uracil DNA glycosylase
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
excision of uracil from U/G mismatches
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
removes uracil from G/U mismatches
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
the glycosylase removes uracil from G/U, C/U, and T/U base pairs faster than it removes thymine from G/T. It can even remove uracil from A/U base pairs, although at a very much lower rate
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
thymine-DNA glycosylase is more active on mismatches containing uracil than on mismatches containing thymine
-
-
?
thymine-guanine mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
-
?
thymine-guanine mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
thiol-modified hairpin probe DNA with 5' overhangs and one mismatched base pair of guanine:thymine in the stem part
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
oligonucleotides with thymine glycol incorporated into different sequence contexts and paired with adenine or guanine. TDG and methyl-CpG-binding protein 4 can remove thymine glycol when present opposite guanine but not when paired with adenine. The efficiency of these enzymes for removal of thymine glycol is about half of that for removal of thymine in the same sequence context. The two proteins may have evolved to act specifically on DNA mismatches produced by deamination and by oxidation-coupled deamination of 5-methylcytosine. This repair pathway contributes to mutation avoidance at methylated CpG dinucleotides
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
in addition to uracil and thymine, the protein can also remove 5-bromouracil from mispairs with guanine
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
the enzyme is capable of removing thymine that has mispaired with 3,N4-ethenocytosine, butanone-ethenocytosine, butanone-ethenoguanine, heptanone-ethenocytosine, or heptanone-ethenoguanine in vitro
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
-
biological role in vivo may also include the correction of a subset of G/U mispairs inefficiently removed by the more abundant ubiquitous uracil glycosylases
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
-
in addition to uracil and thymine, the protein can also remove 5-bromouracil from mispairs with guanine
-
-
?
additional information
?
-
inactivation of TDG significantly increases resistance of human cancer cells towards 5-fluorouracil. Excision of DNA-incorporated 5-fluorouracil by TDG generates persistent DNA strand breaks, delays S-phase progression, and activates DNA damage signaling. The repair of 5-fluorouracilinduced DNA strand breaks is more efficient in the absence of TDG. Excision of 5-fluorouracil by TDG (but not by uracil DNA glycosylases (UNG2 and SMUG1)) prevents efficient downstream processing of the repair intermediate, thereby mediating DNA-directed cytotoxicity
-
-
?
additional information
?
-
-
inactivation of TDG significantly increases resistance of human cancer cells towards 5-fluorouracil. Excision of DNA-incorporated 5-fluorouracil by TDG generates persistent DNA strand breaks, delays S-phase progression, and activates DNA damage signaling. The repair of 5-fluorouracilinduced DNA strand breaks is more efficient in the absence of TDG. Excision of 5-fluorouracil by TDG (but not by uracil DNA glycosylases (UNG2 and SMUG1)) prevents efficient downstream processing of the repair intermediate, thereby mediating DNA-directed cytotoxicity
-
-
?
additional information
?
-
uncertainty about the biological function of TDG. TDG is a DNA glycosylase involved in the repair of damaged DNA bases. Judged from its interactions with other proteins, it is a co-regulator of gene expression
-
-
?
additional information
?
-
human TDG removes the substrate pyrimidines 5-fluorouracil, 5-hydroxymethyluracil, 5-bromouracil, epsilonC and thymine paired with guanine with high relative efficiencies, substrate spectrum and substrate binding structure, overview
-
-
?
additional information
?
-
-
human TDG removes the substrate pyrimidines 5-fluorouracil, 5-hydroxymethyluracil, 5-bromouracil, epsilonC and thymine paired with guanine with high relative efficiencies, substrate spectrum and substrate binding structure, overview
-
-
?
additional information
?
-
TDG interacts with, but also is modified by SUMO-1 and SUMO-3, SUMOylation enhances G-U processing while abolishing G-T processing, mechanism, overview. SUMO modification in the C-terminus converts TDG to an enzyme with Mug-like properties, as does the deletion of the N-terminus, overview
-
-
?
additional information
?
-
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. TDG cleaves the N-glycosylic bond of dT and some other nucleotides, including 5-substituted 2'-deoxyuridine analogues, once they are flipped from the helix into its active site. All of the DNA glycosylases employ nucleotide flipping to extrude the target nucleotide from the helix and gain access to the damaged base and the scissile N-glycosylic bond
-
-
?
additional information
?
-
-
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. TDG cleaves the N-glycosylic bond of dT and some other nucleotides, including 5-substituted 2'-deoxyuridine analogues, once they are flipped from the helix into its active site. All of the DNA glycosylases employ nucleotide flipping to extrude the target nucleotide from the helix and gain access to the damaged base and the scissile N-glycosylic bond
-
-
?
additional information
?
-
TDG cleaves the N-glycosylic bond of dT and some other nucleotides, including 5-substituted 2'-deoxyuridine analogues, once they are flipped from the helix into its active site. Residue Asn140, in motif 138GINPG142, is implicated in the chemical step, does not contribute substantially to substrate binding, and residue Arg275 in nucleotide flipping, Arg275 penetrates the DNA minor groove, filling the void created by nucleotide flipping, active site structure, overview. DNA glycosylases employ nucleotide flipping to extrude the target nucleotide from the helix and gain access to the damaged base and the scissile N-glycosylic bond. The enzyme can also remove 5-halogenated uracils, 5-fluorouracil, 5-chlorouracil, 5-bromouracil, and 5-iodouracil, many other 5-substituted uracils, N4-ethenocytosine, hypoxanthine, and other damaged bases, but not with substrate analogueG:2'-deoxy-2'-fluoroarabinouridine, substrate binding structure and kinetics, overview
-
-
?
additional information
?
-
-
TDG cleaves the N-glycosylic bond of dT and some other nucleotides, including 5-substituted 2'-deoxyuridine analogues, once they are flipped from the helix into its active site. Residue Asn140, in motif 138GINPG142, is implicated in the chemical step, does not contribute substantially to substrate binding, and residue Arg275 in nucleotide flipping, Arg275 penetrates the DNA minor groove, filling the void created by nucleotide flipping, active site structure, overview. DNA glycosylases employ nucleotide flipping to extrude the target nucleotide from the helix and gain access to the damaged base and the scissile N-glycosylic bond. The enzyme can also remove 5-halogenated uracils, 5-fluorouracil, 5-chlorouracil, 5-bromouracil, and 5-iodouracil, many other 5-substituted uracils, N4-ethenocytosine, hypoxanthine, and other damaged bases, but not with substrate analogueG:2'-deoxy-2'-fluoroarabinouridine, substrate binding structure and kinetics, overview
-
-
?
additional information
?
-
the enzyme has negligible affinity for isolated nucleobases
-
-
?
additional information
?
-
the enzyme is degraded in response to DNA damage. UV-induced enzyme degradation is mediated by CRL4(CDT2) E3 ligase which ubiquitinates the enzyme
-
-
?
additional information
?
-
the enzyme removes thymine from mutagenic G-T mispairs caused by 5-methylcytosine deamination and other lesions including uracil and 5-hydroxymethyluracil. In DNA demethylation, the enzyme excises 5-formylcytosine and 5-carboxylcytosine
-
-
?
additional information
?
-
-
DNA repair enzyme specific for G/T mismatches. TDG acts as a transcriptional coactivator, modulates the biological function of p53 family proteins without member specificity
-
-
?
additional information
?
-
-
TDG has a strong preference for uracil over thymine. TDG is an intriguing protein that, similar to SMUG1, has a low turnover number and strong binding to AP sites. The binding of the glycosylase to the AP site inhibits cleavage by the downstream AP endonuclease
-
-
?
additional information
?
-
-
thymine DNA glycosylase and methyl binding domain protein 4 act on G:IU, i.e. iododeoxyuridine, but not A:IU, mispairs and are functionally complementary to each other
-
-
?
additional information
?
-
-
IUdR is a thymidine analogue which has been used in the clinic as a radiosensitizer. Following active cell membrane transport, IUdR is sequentially phosphorylated to IdUTP which competes with thymidine, TdR, for DNA incorporation. G:IU mispair is a substrate for thymidine DNA glycosylase
-
-
?
additional information
?
-
-
TDG has a strong preference for uracil over thymine, it also has a strong preference for U:G mismatches
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
3,N4-ethenocytosine-mismatched double-stranded DNA + H2O
3,N4-ethenocytosine + double-stranded DNA with abasic site
3,N4-ethenocytosine is recognized and efficiently excised by hTDG. The enzyme may be responsible for the repair of this mutagenic lesion in vivo and be important contributors to genetic stability
-
-
?
5-bromouracil-mismatched double-stranded DNA + H2O
5-bromouracil + double-stranded DNA with abasic site
potential role played by human TDG in the cytotoxic effects of 5-chlorouracil and 5-bromouracil incorporation into DNA, which can occur under inflammatory conditions
-
-
?
5-carboxylcytosine mismatched double-stranded DNA + H2O
5-carboxylcytosine + double-stranded DNA with abasic site
-
-
-
?
5-carboxylcytosine-mismatched double-stranded DNA + H2O
5-carboxylcytosine + double-stranded DNA with abasic site
5-chlorouracil-mismatched double-stranded DNA + H2O
5-chlorouracil + double-stranded DNA with abasic site
potential role played by human TDG in the cytotoxic effects of 5-chlorouracil and 5-bromouracil incorporation into DNA, which can occur under inflammatory conditions
-
-
?
5-formylcytosine-mismatched double-stranded DNA + H2O
5-formylcytosine + double-stranded DNA with abasic site
5-hydroxymethyluracil-mismatched double-stranded DNA + H2O
5-hydroxymethyluracil + double-stranded DNA with abasic site
-
-
-
?
5-hydroxymethyluridine-mismatched double-stranded DNA + H2O
5-hydroxymethyluridine + double-stranded DNA with abasic site
-
-
-
?
double-stranded DNA + H2O
?
thymine-DNA glycosylase has a strong sequence preference for CpG sites in the excision of both thymine and ethenocytosine. This suggests a main role of thymine-DNA glycosylase in vivo is the removal of thymine produced by deamination of 5-methylcytosine at CpG sites
-
-
?
thymine-guanine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
uridine-mismatched double-stranded DNA + H2O
uridine + double-stranded DNA with abasic site
-
-
-
?
thymine glycol-mismatched double-stranded DNA + H2O
thymine glycol + double-stranded DNA with abasic site
-
oligonucleotides with thymine glycol incorporated into different sequence contexts and paired with adenine or guanine. TDG and methyl-CpG-binding protein 4 can remove thymine glycol when present opposite guanine but not when paired with adenine. The efficiency of these enzymes for removal of thymine glycol is about half of that for removal of thymine in the same sequence context. The two proteins may have evolved to act specifically on DNA mismatches produced by deamination and by oxidation-coupled deamination of 5-methylcytosine. This repair pathway contributes to mutation avoidance at methylated CpG dinucleotides
-
-
?
thymine-guanine mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
-
biological role in vivo may also include the correction of a subset of G/U mispairs inefficiently removed by the more abundant ubiquitous uracil glycosylases
-
-
?
5-carboxylcytosine-mismatched double-stranded DNA + H2O
5-carboxylcytosine + double-stranded DNA with abasic site
-
-
-
?
5-carboxylcytosine-mismatched double-stranded DNA + H2O
5-carboxylcytosine + double-stranded DNA with abasic site
-
-
-
-
?
5-carboxylcytosine-mismatched double-stranded DNA + H2O
5-carboxylcytosine + double-stranded DNA with abasic site
-
-
-
?
5-formylcytosine-mismatched double-stranded DNA + H2O
5-formylcytosine + double-stranded DNA with abasic site
-
-
-
?
5-formylcytosine-mismatched double-stranded DNA + H2O
5-formylcytosine + double-stranded DNA with abasic site
-
-
-
-
?
5-formylcytosine-mismatched double-stranded DNA + H2O
5-formylcytosine + double-stranded DNA with abasic site
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
about 23% of mutations in hereditary human diseases and 24% of mutations in p53 in human cancers are G to A transitions at sites of cytosine methylation suggesting that these sites are either foci for DNA damage, or foci for damage that is poorly repaired. Thymine produced at these sites by the hydrolytic deamination of 5-methylcytosine is removed by thymine-DNA glycosylase. Thymine-DNA glycosylase also removes 3,N4-ethenocytosine and uracil from DNA. The action of this enzyme is limited by its very low kcat and by tight binding to the apurinic site produced when the thymine is removed. These properties of the enzyme suggest that the inefficiency of the base excision repair pathway that it initiates may be the underlying cause of the prevalence of these mutations
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
the enzyme initiates the repair process by excising the mispaired thymine from the heteroduplex to generate an apyrimidinic site
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
the human enzyme excises thymine and uracil from G-T and G-U mismatches, respectively, and is therefore proposed to play a central role in the cellular defense against genetic mutation through spontaneous deamination of 5-methylcytosine and cytosine
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
-
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
the human enzyme excises thymine and uracil from G-T and G-U mismatches, respectively, and is therefore proposed to play a central role in the cellular defense against genetic mutation through spontaneous deamination of 5-methylcytosine and cytosine
-
-
?
uracil-mismatched double-stranded DNA + H2O
uracil + double-stranded DNA with abasic site
thymine DNA glycosylase may play a backup role to the more efficient general uracil DNA glycosylase
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
-
-
-
?
thymine-mismatched double-stranded DNA + H2O
thymine + double-stranded DNA with abasic site
-
oligonucleotides with thymine glycol incorporated into different sequence contexts and paired with adenine or guanine. TDG and methyl-CpG-binding protein 4 can remove thymine glycol when present opposite guanine but not when paired with adenine. The efficiency of these enzymes for removal of thymine glycol is about half of that for removal of thymine in the same sequence context. The two proteins may have evolved to act specifically on DNA mismatches produced by deamination and by oxidation-coupled deamination of 5-methylcytosine. This repair pathway contributes to mutation avoidance at methylated CpG dinucleotides
-
-
?
additional information
?
-
inactivation of TDG significantly increases resistance of human cancer cells towards 5-fluorouracil. Excision of DNA-incorporated 5-fluorouracil by TDG generates persistent DNA strand breaks, delays S-phase progression, and activates DNA damage signaling. The repair of 5-fluorouracilinduced DNA strand breaks is more efficient in the absence of TDG. Excision of 5-fluorouracil by TDG (but not by uracil DNA glycosylases (UNG2 and SMUG1)) prevents efficient downstream processing of the repair intermediate, thereby mediating DNA-directed cytotoxicity
-
-
?
additional information
?
-
-
inactivation of TDG significantly increases resistance of human cancer cells towards 5-fluorouracil. Excision of DNA-incorporated 5-fluorouracil by TDG generates persistent DNA strand breaks, delays S-phase progression, and activates DNA damage signaling. The repair of 5-fluorouracilinduced DNA strand breaks is more efficient in the absence of TDG. Excision of 5-fluorouracil by TDG (but not by uracil DNA glycosylases (UNG2 and SMUG1)) prevents efficient downstream processing of the repair intermediate, thereby mediating DNA-directed cytotoxicity
-
-
?
additional information
?
-
uncertainty about the biological function of TDG. TDG is a DNA glycosylase involved in the repair of damaged DNA bases. Judged from its interactions with other proteins, it is a co-regulator of gene expression
-
-
?
additional information
?
-
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. TDG cleaves the N-glycosylic bond of dT and some other nucleotides, including 5-substituted 2'-deoxyuridine analogues, once they are flipped from the helix into its active site. All of the DNA glycosylases employ nucleotide flipping to extrude the target nucleotide from the helix and gain access to the damaged base and the scissile N-glycosylic bond
-
-
?
additional information
?
-
-
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. TDG cleaves the N-glycosylic bond of dT and some other nucleotides, including 5-substituted 2'-deoxyuridine analogues, once they are flipped from the helix into its active site. All of the DNA glycosylases employ nucleotide flipping to extrude the target nucleotide from the helix and gain access to the damaged base and the scissile N-glycosylic bond
-
-
?
additional information
?
-
-
TDG has a strong preference for uracil over thymine. TDG is an intriguing protein that, similar to SMUG1, has a low turnover number and strong binding to AP sites. The binding of the glycosylase to the AP site inhibits cleavage by the downstream AP endonuclease
-
-
?
additional information
?
-
-
thymine DNA glycosylase and methyl binding domain protein 4 act on G:IU, i.e. iododeoxyuridine, but not A:IU, mispairs and are functionally complementary to each other
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
sumoylation dramatically impairs the enzyme's base-excision activity, such that guanine-thymine activity is reduced by more than 45fold and 5-formylcytosine and 5-carboxylcytosine are excised slowly, with a reaction half-life of more than 9 min at 37°C
-
additional information
-
no inhibition of TDG activity on methylated G:IU mispairs by the methyl binding domain
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SUMO-1
TDG interacts with, but also is modified by SUMO-1 and SUMO-3, SUMOs are small ubiquitin like modifiers, small polypeptides structurally related to ubiquitin that interact with and/or are attached to other proteins. SUMO conjugation involves Lys330 located in a C-terminal SUMOylation consensus motif, VKEE, it is ATP-dependent and, when performed in cell extracts, stimulated by the presence of DNA. SUMO attachment to K330 affects structural and enzymatic properties of TDG. The modified glycosylase is not longer able to interact with free SUMO or SUMO-conjugated proteins, or to bind stably to AP-sites or any other DNA. Yet, it processes a G-U substrate with enhanced efficiency due to an induced enzymatic turnover but, at the same time, loses its ability to hydrolyze T from a G-T substrate
-
SUMO-3
TDG interacts with, but also is modified by SUMO-1 and SUMO-3, SUMOs are small ubiquitin like modifiers, small polypeptides structurally related to ubiquitin that interact with and/or are attached to other proteins. SUMO conjugation involves Lys330 located in a C-terminal SUMOylation consensus motif, VKEE, it is ATP-dependent and, when performed in cell extracts, stimulated by the presence of DNA. SUMO attachment to K330 affects structural and enzymatic properties of TDG. The modified glycosylase is not longer able to interact with free SUMO or SUMO-conjugated proteins, or to bind stably to AP-sites or any other DNA. Yet, it processes a G-U substrate with enhanced efficiency due to an induced enzymatic turnover but, at the same time, loses its ability to hydrolyze T from a G-T substrate
-
additional information
AP andonuclease 1 is able to stimulate the turnover of TDG on a G/T substrate
-
additional information
the enzyme can be stimulated by human AP endonuclease 1
-
additional information
-
the enzyme can be stimulated by human AP endonuclease 1
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0000243
3,N4-ethenocytosine-mismatched double-stranded DNA
excision of 3,N4-ethenocytosine from 3,N4-ethenocytidine/G mismatches
-
0.0000128
thymine-mismatched double-stranded DNA
excision of thymine from T/G mismatches
-
0.000012
uracil-mismatched double-stranded DNA
excision of uracil from U/G mismatches
-
additional information
additional information
pre-steady-state kinetics, and minimal kinetic mechanism for TDG, single turnover kinetics, detailed, overview
-
additional information
additional information
-
pre-steady-state kinetics, and minimal kinetic mechanism for TDG, single turnover kinetics, detailed, overview
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000153
3,N4-ethenocytosine-mismatched double-stranded DNA
excision of 3,N4-ethenocytosine from 3,N4-ethenocytidine/G mismatches
-
2.1
5-chlorouracil-mismatched double-stranded DNA
cleavage of 5-chlorouracil from G/5-chlorouracil mismatch
-
3.7
5-fluorouracil-mismatched double-stranded DNA
cleavage of 5-fluorouracil from G/5-fluorouracil mismatch
-
0.000015
thymine-mismatched double-stranded DNA
excision of thymine from T/G mismatches
-
0.0036
thymine-mismatched double-stranded DNA
cleavage of thymine from G/T mismatch
-
0.00035
uracil-mismatched double-stranded DNA
excision of uracil from U/G mismatches
-
0.043
uracil-mismatched double-stranded DNA
cleavage of uracil from G/U mismatch
-
additional information
additional information
effect of the 5'-flanking base pair on kcat
-
additional information
additional information
-
effect of the 5'-flanking base pair on kcat
-
additional information
additional information
the 5'-flanking base pair to G/T mismatches influences the rate of removal of thymine from G/T mismatch: kcat values with C/G, T/A, G/C, and A/T as the 5'-base pair are 0.91, 0.023, 0.0046, and 0.0013 per min, respectively. kcat values for removal of thymine from S6-methylthioguanine/T with C/G, T/A, G/C, and A/T as the 5'-base pair are 0.026, 0.018, 0.0017, and 0.0010 min, respectively
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
glycosylase activity of the recombinant enzyme, differential G-T processing, overview
additional information
-
glycosylase activity of the recombinant enzyme, differential G-T processing, overview
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
in untransfected MCF-7 cells, endogenous TDG staining is observed in a granular pattern throughout the nucleoplasm. A subpopulation of cells consistently displays increased staining within the promyelocytic leukemia protein oncogenic domains. SUMO-1 binding activity of TDG may be required for targeting to these nuclear structures. Sumoylation of TDG regulates association with CREB-binding protein and subnuclear localization
additional information
-
TDG is strictly cell-cycle regulated. TDG is regulated, opposite to UNG2, EC 3.2.2.27, by displaying the highest expression in the G1-phase and the lowest in the S-phase
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
in untransfected MCF-7 cells, endogenous TDG staining is observed in a granular pattern throughout the nucleoplasm. A subpopulation of cells consistently displays increased staining within the promyelocytic leukemia protein oncogenic domains. SUMO-1 binding activity of TDG may be required for targeting to these nuclear structures
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
the enzyme interacts with the CH3 domain of histone acetyltransferase p300 to allosterically promote p300 activity to specific lysines on histone H3 (K18 and K23). The absence of the enzyme in mouse embryonic fibroblasts leads to a reduction in the rate of histone acetylation
physiological function
malfunction
physiological function
physiological function
ectopic enzyme expression compromises cellular survival after UV irradiation and repair of UV-induced DNA lesions
physiological function
when enzyme concentrations approach those of histones, the enzyme acts as a competitive inhibitor of p300 histone acetylation
malfunction
-
enzyme knockdown by shRNAs inhibits the proliferation of colorectal cancer cells in vitro and in vivo
malfunction
-
enzyme-knockdown cells exhibit higher resistance to cell death caused by the induction of etheno-DNA adducts, lower repair activityfor 3,N4-ethenocytosine, and a modest acceleration of mutations caused by 3,N4-ethenocytosine,compared with the rate in control cells
malfunction
-
enzyme knockdown in melanoma cell lines causes cell cycle arrest, senescence, and death by mitotic alterations, alters the transcriptome and methylome, and impairs xenograft tumor formation
physiological function
-
TDG seems not to have an important function in uracil repair compared with the leading enzymes UNG2 and SMUG1, EC 3.2.2.27
physiological function
-
the enzyme does not affect HBV replication, but the hepatitis B virus X-protein strongly inhibits enzyme-initiated base excision repair
physiological function
-
the enzyme plays key roles in sustaining genome integrity because of its ability to selectively remove thymine from G/T mismatches through the DNA base excision repair pathway. The enzyme is actively involved in epigenetic regulation by participating in the DNA 5-methylcytosine demethylation processes
physiological function
-
the enzyme shows repair activities toward etheno-DNA adducts
physiological function
-
thymine DNA glycosylase up-regulates Wnt signaling by interacting with the transcription factor TCF4 and coactivator CREB-binding protein/p300 in the Wnt pathway
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). TDG_HUMAN
410
0
46053
Swiss-Prot
other Location (Reliability: 1)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
primary and domain structure, tertiary structure and structure-function analysis, overview
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
TDG catalytic efficiency of the protein is increased by SUMOylation
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystal structure of hTDG (catalytic domain, hTDGcat) in complex with abasic DNA, at 2.8 A resolution. The enzyme crystallizes in a 2:1 complex with DNA, one subunit bound at the abasic site, and the other at an undamaged (nonspecific) site
crystals of SUMO-1TDG complex are grown in 25% PEG 3350, 0.2 M MgCl2 and 0.1 M Tris-HCl (pH 8.5) at 20°C by using a micro-seeding technique. Crystal structure of the central region of human TDG conjugated to SUMO-1 at 2.1 A resolution
crystals of SUMO-3TDG are grown in 1.5 M sodium malonate (pH 5.0) at 20°C, by using a streaking technique. Crystal structure of the central region of TDG conjugated to SUMO-3
enzyme bound to DNA with a non-cleavable (2'-fluoroarabino) analog of 5-formyldeoxycytidine flipped into its active site
enzyme construct TDG82-308, sitting drop vapor diffusion method, using 30% (w/v) PEG 4000, 0.2 M ammonium acetate, 0.1 M sodium acetate, pH 6.0
free enzyme and in complex with DNA, sitting drop vapor diffusion method, using 30% (w/v) PEG 4000, 0.2 M ammonium acetate, 0.1 M sodium acetate, pH 6.0
in complex with a 28-base pair DNA containing a guanine:5-hydroxymethyluracil mismatch, hanging drop vapor diffusion method, using 30% (w/v) polyethylene glycol 4000, 0.2 M ammonium acetate, 0.1 M sodium acetate, pH 4.6
in complex with duplex DNA containing either 5-carboxylcytosine or a 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-carbonylcytosine, hanging drop vapor diffusion method, using
mutant N140A in complex with guanine:5-carboxylcytosine containing DNA, using 30% (w/v) polyethylene glycol 4000, 0.2 M ammonium acetate, 0.1 M sodium acetate, pH 4.6
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
H151A
N140A
N140A/R275L
site-directed mutagenesis, altered kinetics compared to the wild-type enzyme, overview
N140D
the mutant exhibits 96fold and 5fold reduced activity at pH 6.0 after 24 h for guanine:uracil and after 72 h for guanine:5-carboxylcytosine, respectively
N140D/N157D
the mutant exhibits no activity for DNA containing guanine:uracil and guanine:5-carboxylcytosine pairs
N157A
the mutant exhibits 6fold and 3fold reduced activity at pH 6.0 after 24 h for guanine:uracil and after 72 h for guanine:5-carboxylcytosine, respectively
N157D
the mutant exhibits 1350fold and 1.1fold reduced activity at pH 6.0 after 24 h for guanine:uracil and after 72 h for guanine:5-carboxylcytosine, respectively
N157D/N230D
the mutant exhibits 135fold reduced activity and no activity at pH 6.0 after 24 h for guanine:uracil and after 72 h for guanine:5-carboxylcytosine, respectively
N230D
the mutant exhibits 32fold and 3fold reduced activity at pH 6.0 after 24 h for guanine:uracil and after 72 h for guanine:5-carboxylcytosine, respectively
R275A
site-directed mutagenesis, altered kinetics compared to the wild-type enzyme, overview
R275L
site-directed mutagenesis, altered kinetics compared to the wild-type enzyme, overview
T197A
D133A
-
the mutation significantly reduces the enzymes ability to enhance Wnt signaling
H151A
the mutant shows increased transition rates and activity compared to the wild type enzyme
N140A
site-directed mutagenesis, the mutant variant binds substrate DNA with the same tight affinity as wild-type TDG, but it has no detectable base excision activity for a G:T substrate, and its excision rate is vastly diminished for G:U, G:FU, i.e. fluorouridine, and G:BrU, i.e. bromodeoxyuridine, substrates. Altered kinetics compared to the wild-type enzyme, overview
N140A
the mutant exhibits 1800fold and more than 20000fold reduced activity at pH 6.0 after 24 h for guanine:uracil and after 72 h for guanine:5-carboxylcytosine, respectively
N140A
the mutation completely depletes guanine-thymine glycosylase activity and causes a huge (27000fold) loss in guanine-uracil activity
T197A
the mutation causes a 32fold reduction in guanine-thymine glycosylase activity
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
cDNA sequence encoding human TDG (residues 112339) is subcloned into a pGEX4T-3 vector. SUMO-3-modified TDG112339 (SUMO-3TDG) is expressed bacterially using an Escherichia coli SUMOylation system by co-transforming the Escherichia coli strain BL21(DE3) with TDG112339/pGEX4T-3 and pT-E1E2S2 protein expression vectors
nickel-charged chelating column chromatography, HiTrap SP column chromatography, and Superdex 75 gel filtration
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
DNA and amino acid sequence determination and analysis, phylogenetic tree of MUG proteins, expression in African green monkey kidney cells, the enzyme efficiently replaces the T with a C in G-T mismatched SV40 DNA exhibiting a G-T directed repair activity
expressed in Escherichia coli strain BL21 (DE3), MEF cells and HEK-293T cells
HeLa cell clones either stably transfected with a construct overexpressing human TDG from a cytomegalovirus promoter or with the corresponding vector only
phylogenetic analysis, expression of His-tagged TDG in Escherichia coli strain BL21 (DE3)
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
in colorectal cancer patients, enzyme levels are significantly higher in tumor tissues than in the adjacent normal tissues
-
wild type p53 binds to a domain of the enzyme promoter containing two p53 consensus response elements and activates its transcription
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
5-fluorouracil is used in clinical cancer therapy. The status of TDG expression in a cancer is likely to determine its response to 5-fluorouracil-based chemotherapy
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Kim, E.-J.; Um, S.-J.
Thymine-DNA glycosylase interacts with and functions as a coactivator of p53 family proteins
Biochem. Biophys. Res. Commun.
377
838-842
2008
Homo sapiens
Sibghat-Ullah; Gallinari, P.; Xu, Y.Z.; Goodman, M.F.; Bloom, L.B.; Jiricny, J.; Day, R.S. 3rd.
Base analog and neighboring base effects on substrate specificity of recombinant human G:T mismatch-specific thymine DNA-glycosylase
Biochemistry
35
12926-12932
1996
Homo sapiens (Q13569), Homo sapiens
Neddermann, P.; Gallinari, P.; Lettieri, T.; Schmid, D.; Truong, O.; Hsuan, J.J.; Wiebauer, K.; Jiricny, J.
Cloning and expression of human G/T mismatch-specific thymine-DNA glycosylase
Biol. Chem.
271
12767-12774
1996
Homo sapiens (Q13569), Homo sapiens
Hang, B.; Guliaev, A.B.
Substrate specificity of human thymine-DNA glycosylase on exocyclic cytosine adducts
Chem. Biol. Interact.
165
230-238
2007
Homo sapiens (Q13569), Homo sapiens
Cortazar, D.; Kunz, C.; Saito, Y.; Steinacher, R.; Schr, P.
The enigmatic thymine DNA glycosylase
DNA Repair
6
489-504
2007
Homo sapiens (Q13569)
Bennett, M.T.; Rodgers, M.T.; Hebert, A.S.; Ruslander, L.E.; Eisele, L.; Drohat, A.C.
Specificity of human thymine DNA glycosylase depends on N-glycosidic bond stability
J. Am. Chem. Soc.
128
12510-12519
2006
Homo sapiens (Q13569), Homo sapiens
Neddermann, P.; Jiricny, J.
The purification of a mismatch-specific thymine-DNA glycosylase from HeLa cells
J. Biol. Chem.
268
21218-21224
1993
Homo sapiens (Q13569)
Waters, T.R.
Swann, P.F.: Kinetics of the action of thymine DNA glycosylase
J. Biol. Chem.
273
20007-20014
1998
Homo sapiens (Q13569)
Abu, M.; Waters, T.R.
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
8739-8744
2003
Homo sapiens (Q13569), Homo sapiens
Morgan, M.T.; Bennett, M.T.; Drohat, A.C.
Excision of 5-halogenated uracils by human thymine DNA glycosylase. Robust activity for DNA contexts other than CpG
J. Biol. Chem.
282
27578-27586
2007
Homo sapiens (Q13569), Homo sapiens
Baba, D.; Maita, N.; Jee, J.G.; Uchimura, Y.; Saitoh, H.; Sugasawa, K.; Hanaoka, F.; Tochio, H.; Hiroaki, H.; Shirakawa, M.
Crystal structure of SUMO-3-modified thymine-DNA glycosylase
J. Mol. Biol.
359
137-147
2006
Homo sapiens (Q13569)
Mohan, R.D.; 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.
27
229-243
2007
Homo sapiens (Q13569)
Waters, T.R.; Swann, P.F.
Thymine-DNA glycosylase and G to A transition mutations at CpG sites
Mutat. Res.
462
137-147
2000
Homo sapiens (Q13569), Homo sapiens
Baba, D.; Maita, N.; Jee, J.G.; Uchimura, Y.; Saitoh, H.; Sugasawa, K.; Hanaoka. F.; Tochio, H.; Hiroaki, H.; Shirakawa, M.
Crystal structure of thymine DNA glycosylase conjugated to SUMO-1.
Nature
435
979-982
2005
Homo sapiens (Q13569), Homo sapiens
Hardeland, U.; Bentele, M.; Jiricny, J.; Schaer, P.
The versatile thymine DNA-glycosylase: a comparative characterization of the human, Drosophila and fission yeast orthologs
Nucleic Acids Res.
31
2261-2271
2003
Drosophila melanogaster (Q9V4D8), Drosophila melanogaster, Homo sapiens (Q13569), Homo sapiens
Yoon, J.H.; Iwai, S.; O'Connor, T.R.; Pfeifer, G.P.
Human thymine DNA glycosylase (TDG) and methyl-CpG-binding protein 4 (MBD4) excise thymine glycol (Tg) from a Tg:G mispair
Nucleic Acids Res.
31
5399-5404
2003
Homo sapiens
Kunz, C.; Focke, F.; Saito, Y.; Schuermann, D.; Lettieri, T.; Selfridge, J.; Schr, P.
Base excision by thymine DNA glycosylase mediates DNA-directed cytotoxicity of 5-fluorouracil
PLoS Biol.
7
e91
2009
Homo sapiens (Q13569), Homo sapiens
Maiti, A.; Morgan, M.T.; Pozharski, E.; Drohat, A.C.
Crystal structure of human thymine DNA glycosylase bound to DNA elucidates sequence-specific mismatch recognition
Proc. Natl. Acad. Sci. USA
105
8890-8895
2008
Homo sapiens (Q13569), Homo sapiens
Neddermann, P.; Jiricny, J.
Efficient removal of uracil from GNU mispairs by the mismatch-specific thymine DNA glycosylase from HeLa cells
Proc. Natl. Acad. Sci. USA
91
1642-1646
1994
Homo sapiens
Saparbaev, M.; Laval, J.
3,N4-ethenocytosine, a highly mutagenic adduct, is a primary substrate for Escherichia coli double-stranded uracil-DNA glycosylase and human mismatch-specific thymine-DNA glycosylase
Proc. Natl. Acad. Sci. USA
95
8508-8513
1998
Homo sapiens (Q13569), Homo sapiens
Aziz, M.A.; Schupp, J.E.; Kinsella, T.J.
Modulation of the activity of methyl binding domain protein 4 (MBD4/MED1) while processing iododeoxyuridine generated DNA mispairs
Cancer Biol. Ther.
8
1156-1163
2009
Homo sapiens
Maiti, A.; Morgan, M.T.; Drohat, A.C.
Role of two strictly conserved residues in nucleotide flipping and N-glycosylic bond cleavage by human thymine DNA glycosylase
J. Biol. Chem.
284
36680-36688
2009
Homo sapiens (Q13569), Homo sapiens
Visnes, T.; Doseth, B.; Pettersen, H.; Hagen, L.; Sousa, M.; Akbari, M.; Otterlei, M.; Kavli, B.; Slupphaug, G.; Krokan, H.
Uracil in DNA and its processing by different DNA glycosylases
Philos. Trans. R. Soc. Lond. B Biol. Sci.
364
563-568
2009
Homo sapiens, Mus musculus
da Costa, N.M.; Hautefeuille, A.; Cros, M.P.; Melendez, M.E.; Waters, T.; Swann, P.; Hainaut, P.; Pinto, L.F.
Transcriptional regulation of thymine DNA glycosylase (TDG) by the tumor suppressor protein p53
Cell Cycle
11
4570-4578
2012
Homo sapiens
Chen, C.; Zhou, D.; Tang, H.; Liang, M.; Jiang, J.
A sensitive, homogeneous fluorescence assay for detection of thymine DNA glycosylase activity based on exonuclease-mediated amplification
Chem. Commun. (Camb. )
49
5874-5876
2013
Homo sapiens
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
12
535-540
2013
Homo sapiens (Q13569), Homo sapiens
Goto, M.; Shinmura, K.; Matsushima, Y.; Ishino, K.; Yamada, H.; Totsuka, Y.; Matsuda, T.; Nakagama, H.; Sugimura, H.
Human DNA glycosylase enzyme TDG repairs thymine mispaired with exocyclic etheno-DNA adducts
Free Radic. Biol. Med.
76
136-146
2014
Homo sapiens
Xu, X.; Yu, T.; Shi, J.; Chen, X.; Zhang, W.; Lin, T.; Liu, Z.; Wang, Y.; Zeng, Z.; Wang, C.; Li, M.; Liu, C.
Thymine DNA glycosylase is a positive regulator of Wnt signaling in colorectal cancer
J. Biol. Chem.
289
8881-8890
2014
Homo sapiens
Zhang, L.; Lu, X.; Lu, J.; Liang, H.; Dai, Q.; Xu, G.L.; Luo, C.; Jiang, H.; He, C.
Thymine DNA glycosylase specifically recognizes 5-carboxylcytosine-modified DNA
Nat. Chem. Biol.
8
328-330
2012
Homo sapiens (Q13569), Homo sapiens
Hashimoto, H.; Hong, S.; Bhagwat, A.S.; 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.
40
10203-10214
2012
Homo sapiens (Q13569), Homo sapiens
van de Klundert, M.A.; van Hemert, F.J.; Zaaijer, H.L.; Kootstra, N.A.
The hepatitis B virus X protein inhibits thymine DNA glycosylase initiated base excision repair
PLoS ONE
7
e48940
2012
Homo sapiens
Bai, W.; Wei, Y.; Zhang, Y.; Bao, L.; Li, Y.
Label-free and amplified electrogenerated chemiluminescence biosensing for the detection of thymine DNA glycosylase activity using DNA-functionalized gold nanoparticles triggered hybridization chain reaction
Anal. Chim. Acta
1061
101-109
2019
Homo sapiens
Pidugu, L.S.; Flowers, J.W.; Coey, C.T.; Pozharski, E.; Greenberg, M.M.; Drohat, A.C.
Structural basis for excision of 5-formylcytosine by thymine DNA glycosylase
Biochemistry
55
6205-6208
2016
Homo sapiens (Q13569)
Henry, R.A.; Mancuso, P.; Kuo, Y.M.; Tricarico, R.; Tini, M.; Cole, P.A.; Bellacosa, A.; Andrews, A.J.
Interaction with the DNA repair protein thymine DNA glycosylase regulates histone acetylation by p300
Biochemistry
55
6766-6775
2016
Homo sapiens (Q13569)
Kanaan, N.; Imhof, P.
Interactions of the DNA repair enzyme human thymine DNA glycosylase with cognate and noncognate DNA
Biochemistry
57
5654-5665
2018
Homo sapiens (Q13569), Homo sapiens
Wang, L.J.; Wang, Z.Y.; Zhang, Q.; Tang, B.; Zhang, C.Y.
Cyclic enzymatic repairing-mediated dual-signal amplification for real-time monitoring of thymine DNA glycosylase
Chem. Commun. (Camb.)
53
3878-3881
2017
Homo sapiens
Nakamura, T.; Murakami, K.; Tada, H.; Uehara, Y.; Nogami, J.; Maehara, K.; Ohkawa, Y.; Saitoh, H.; Nishitani, H.; Ono, T.; Nishi, R.; Yokoi, M.; Sakai, W.; Sugasawa, K.
Thymine DNA glycosylase modulates DNA damage response and gene expression by base excision repair-dependent and independent mechanisms
Genes Cells
22
392-405
2017
Homo sapiens (Q13569)
Kanaan, N.; Crehuet, R.; Imhof, P.
Mechanism of the glycosidic bond cleavage of mismatched thymine in human thymine DNA glycosylase revealed by classical molecular dynamics and quantum mechanical/molecular mechanical calculations
J. Phys. Chem. B
119
12365-12380
2015
Homo sapiens (Q13569), Homo sapiens
Naydenova, E.; Dietschreit, J.C.B.; Ochsenfeld, C.
Reaction mechanism for the N-glycosidic bond cleavage of 5-formylcytosine by thymine DNA glycosylase
J. Phys. Chem. B
123
4173-4179
2019
Homo sapiens (Q13569)
Malik, S.S.; Coey, C.T.; Varney, K.M.; Pozharski, E.; Drohat, A.C.
Thymine DNA glycosylase exhibits negligible affinity for nucleobases that it removes from DNA
Nucleic Acids Res.
43
9541-9552
2015
Homo sapiens (Q13569)
Coey, C.T.; Malik, S.S.; Pidugu, L.S.; Varney, K.M.; Pozharski, E.; Drohat, A.C.
Structural basis of damage recognition by thymine DNA glycosylase Key roles for N-terminal residues
Nucleic Acids Res.
44
10248-10258
2016
Homo sapiens (Q13569)
Coey, C.T.; Drohat, A.C.
Defining the impact of sumoylation on substrate binding and catalysis by thymine DNA glycosylase
Nucleic Acids Res.
46
5159-5170
2018
Homo sapiens (Q13569)
Mancuso, P.; Tricarico, R.; Bhattacharjee, V.; Cosentino, L.; Kadariya, Y.; Jelinek, J.; Nicolas, E.; Einarson, M.; Beeharry, N.; Devarajan, K.; Katz, R.A.; Dorjsuren, D.G.; Sun, H.; Simeonov, A.; Giordano, A.; Testa, J.R.; Davidson, G.; Davidson, I.; Larue, L.; Sobol, R.W.; Yen, T.J.; Bellacosa, A.
Thymine DNA glycosylase as a novel target for melanoma
Oncogene
38
3710-3728
2019
Homo sapiens
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