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Q13569 (TDG_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 125. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
G/T mismatch-specific thymine DNA glycosylase

EC=3.2.2.29
Alternative name(s):
Thymine-DNA glycosylase
Short name=hTDG
Gene names
Name:TDG
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length410 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

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. Ref.1 Ref.5 Ref.6 Ref.9 Ref.14 Ref.15 Ref.16

Catalytic activity

Hydrolyzes mismatched double-stranded DNA and polynucleotides, releasing free thymine.

Subunit structure

Homodimer. Interacts with AICDA and GADD45A. Ref.8 Ref.13 Ref.14

Subcellular location

Nucleus Ref.1.

Post-translational modification

Sumoylation on Lys-330 by either SUMO1 or SUMO2 induces dissociation of the product DNA. Ref.7

Sequence similarities

Belongs to the TDG/mug DNA glycosylase family.

Ontologies

Keywords
   Biological processDNA damage
DNA repair
Transcription
Transcription regulation
   Cellular componentNucleus
   Coding sequence diversityPolymorphism
   Molecular functionActivator
Chromatin regulator
Glycosidase
Hydrolase
   PTMIsopeptide bond
Ubl conjugation
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processDNA demethylation

Inferred from sequence or structural similarity. Source: UniProtKB

DNA repair

Traceable author statement. Source: Reactome

base-excision repair

Inferred from direct assay Ref.9Ref.14. Source: UniProtKB

base-excision repair, AP site formation

Traceable author statement. Source: Reactome

chromatin modification

Inferred from electronic annotation. Source: UniProtKB-KW

depyrimidination

Traceable author statement. Source: Reactome

embryo development

Inferred from sequence or structural similarity. Source: UniProtKB

mismatch repair

Inferred from direct assay Ref.16. Source: UniProtKB

negative regulation of chromatin binding

Inferred from electronic annotation. Source: Ensembl

negative regulation of protein binding

Inferred from electronic annotation. Source: Ensembl

negative regulation of transcription from RNA polymerase II promoter

Inferred from electronic annotation. Source: Ensembl

regulation of gene expression, epigenetic

Inferred from sequence or structural similarity. Source: UniProtKB

   Cellular_componentPML body

Inferred from electronic annotation. Source: Ensembl

nucleoplasm

Traceable author statement. Source: Reactome

nucleus

Inferred from direct assay Ref.1. Source: UniProtKB

plasma membrane

Inferred from direct assay. Source: HPA

   Molecular_functionDNA N-glycosylase activity

Inferred from direct assay Ref.9Ref.14. Source: UniProtKB

RNA polymerase II transcription cofactor activity

Inferred from electronic annotation. Source: Ensembl

damaged DNA binding

Traceable author statement PubMed 9489705. Source: ProtInc

double-stranded DNA binding

Inferred from direct assay Ref.14. Source: UniProtKB

mismatched DNA binding

Inferred from direct assay Ref.16. Source: UniProtKB

protein binding

Inferred from physical interaction Ref.8. Source: IntAct

protein homodimerization activity

Inferred from direct assay Ref.14. Source: UniProtKB

pyrimidine-specific mismatch base pair DNA N-glycosylase activity

Inferred from direct assay Ref.16Ref.1. Source: UniProtKB

structure-specific DNA binding

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

AICDAQ9GZX75EBI-348333,EBI-3834328
GADD45AP245223EBI-348333,EBI-448167

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 410410G/T mismatch-specific thymine DNA glycosylase
PRO_0000185777

Amino acid modifications

Cross-link330Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO) Ref.7

Natural variations

Natural variant1991G → S. Ref.2
Corresponds to variant rs4135113 [ dbSNP | Ensembl ].
VAR_018892
Natural variant3671V → L.
Corresponds to variant rs2888805 [ dbSNP | Ensembl ].
VAR_059450
Natural variant3671V → M. Ref.2
Corresponds to variant rs2888805 [ dbSNP | Ensembl ].
VAR_018893
Natural variant3811G → E.
Corresponds to variant rs3953597 [ dbSNP | Ensembl ].
VAR_050140

Experimental info

Mutagenesis1401N → A: Loss of DNA glycosylase activity but still able to bind DNA. Ref.14
Mutagenesis1451A → G: Increased DNA glycosylase activity on G/T mispairs. Ref.16
Mutagenesis1511H → A or Q: Increased DNA glycosylase activity on G/T mispairs. Ref.16
Mutagenesis1911N → A: Reduced DNA glycosylase activity on G/T and G/U mispairs. Ref.16
Mutagenesis1971T → A: Reduced DNA glycosylase activity on G/T mispairs. Ref.16
Mutagenesis2811R → A: Restores the DNA-binding ability of the sumoylated form. Ref.11
Mutagenesis3101E → Q: Restores the DNA-binding ability of the sumoylated form. Ref.11 Ref.12
Mutagenesis3151F → A: Restores the DNA-binding ability of the sumoylated form. Ref.11
Sequence conflict911S → P in AAC50540. Ref.1
Sequence conflict2681V → G in AAH37557. Ref.4

Secondary structure

.......................................... 410
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q13569 [UniParc].

Last modified April 13, 2004. Version 2.
Checksum: 33752B26EBC789AE

FASTA41046,053
        10         20         30         40         50         60 
MEAENAGSYS LQQAQAFYTF PFQQLMAEAP NMAVVNEQQM PEEVPAPAPA QEPVQEAPKG 

        70         80         90        100        110        120 
RKRKPRTTEP KQPVEPKKPV ESKKSGKSAK SKEKQEKITD TFKVKRKVDR FNGVSEAELL 

       130        140        150        160        170        180 
TKTLPDILTF NLDIVIIGIN PGLMAAYKGH HYPGPGNHFW KCLFMSGLSE VQLNHMDDHT 

       190        200        210        220        230        240 
LPGKYGIGFT NMVERTTPGS KDLSSKEFRE GGRILVQKLQ KYQPRIAVFN GKCIYEIFSK 

       250        260        270        280        290        300 
EVFGVKVKNL EFGLQPHKIP DTETLCYVMP SSSARCAQFP RAQDKVHYYI KLKDLRDQLK 

       310        320        330        340        350        360 
GIERNMDVQE VQYTFDLQLA QEDAKKMAVK EEKYDPGYEA AYGGAYGENP CSSEPCGFSS 

       370        380        390        400        410 
NGLIESVELR GESAFSGIPN GQWMTQSFTD QIPSFSNHCG TQEQEEESHA 

« Hide

References

« Hide 'large scale' references
[1]"Cloning and expression of human G/T mismatch-specific thymine-DNA glycosylase."
Neddermann P., Gallinari P., Lettieri T., Schmid D., Truong O., Hsuan J.J., Wiebauer K., Jiricny J.
J. Biol. Chem. 271:12767-12774(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE, FUNCTION, SUBCELLULAR LOCATION.
[2]NIEHS SNPs program
Submitted (SEP-2002) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS SER-199 AND MET-367.
[3]"The finished DNA sequence of human chromosome 12."
Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R. expand/collapse author list , Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K., Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D., Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J., Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A., Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M., Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I., Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A., Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G., Gibbs R.A.
Nature 440:346-351(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Colon.
[5]"Efficient removal of uracil from G.U mispairs by the mismatch-specific thymine DNA glycosylase from HeLa cells."
Neddermann P., Jiricny J.
Proc. Natl. Acad. Sci. U.S.A. 91:1642-1646(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[6]"The purification of a mismatch-specific thymine-DNA glycosylase from HeLa cells."
Neddermann P., Jiricny J.
J. Biol. Chem. 268:21218-21224(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[7]"Modification of the human thymine-DNA glycosylase by ubiquitin-like proteins facilitates enzymatic turnover."
Hardeland U., Steinacher R., Jiricny J., Schaer P.
EMBO J. 21:1456-1464(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: SUMOYLATION AT LYS-330.
[8]"Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair."
Cortellino S., Xu J., Sannai M., Moore R., Caretti E., Cigliano A., Le Coz M., Devarajan K., Wessels A., Soprano D., Abramowitz L.K., Bartolomei M.S., Rambow F., Bassi M.R., Bruno T., Fanciulli M., Renner C., Klein-Szanto A.J. expand/collapse author list , Matsumoto Y., Kobi D., Davidson I., Alberti C., Larue L., Bellacosa A.
Cell 146:67-79(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH AICDA AND GADD45A.
[9]"Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: potential implications for active demethylation of CpG sites."
Maiti A., Drohat A.C.
J. Biol. Chem. 286:35334-35338(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[10]"N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB."
Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.
Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[11]"Crystal structure of thymine DNA glycosylase conjugated to SUMO-1."
Baba D., Maita N., Jee J.-G., Uchimura Y., Saitoh H., Sugasawa K., Hanaoka F., Tochio H., Hiroaki H., Shirakawa M.
Nature 435:979-982(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 112-339 CONJUGATED TO SUMO1, MUTAGENESIS OF ARG-281; GLU-310 AND PHE-315.
[12]"Crystal structure of SUMO-3-modified thymine-DNA glycosylase."
Baba D., Maita N., Jee J.-G., Uchimura Y., Saitoh H., Sugasawa K., Hanaoka F., Tochio H., Hiroaki H., Shirakawa M.
J. Mol. Biol. 359:137-147(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 112-339 CONJUGATED TO SUMO2, MUTAGENESIS OF GLU-310.
[13]"Crystal structure of human thymine DNA glycosylase bound to DNA elucidates sequence-specific mismatch recognition."
Maiti A., Morgan M.T., Pozharski E., Drohat A.C.
Proc. Natl. Acad. Sci. U.S.A. 105:8890-8895(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.79 ANGSTROMS) OF 111-308 IN COMPLEX WITH DNA, SUBUNIT.
[14]"Thymine DNA glycosylase specifically recognizes 5-carboxylcytosine-modified DNA."
Zhang L., Lu X., Lu J., Liang H., Dai Q., Xu G.L., Luo C., Jiang H., He C.
Nat. Chem. Biol. 8:328-330(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (3.01 ANGSTROMS) OF 111-308 IN COMPLEX WITH DNA, FUNCTION, SUBUNIT, MUTAGENESIS OF ASN-140.
[15]"Excision of 5-hydroxymethyluracil and 5-carboxylcytosine by the thymine DNA glycosylase domain: its structural basis and implications for active DNA demethylation."
Hashimoto H., Hong S., Bhagwat A.S., Zhang X., Cheng X.
Nucleic Acids Res. 40:10203-10214(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.49 ANGSTROMS) OF 111-308 IN COMPLEX WITH DNA, FUNCTION.
[16]"Lesion processing by a repair enzyme is severely curtailed by residues needed to prevent aberrant activity on undamaged DNA."
Maiti A., Noon M.S., MacKerell A.D. Jr., Pozharski E., Drohat A.C.
Proc. Natl. Acad. Sci. U.S.A. 109:8091-8096(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.97 ANGSTROMS) OF 111-308 IN COMPLEX WITH DNA, FUNCTION, MUTAGENESIS OF ALA-145; HIS-151; ASN-191 AND THR-197.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U51166 mRNA. Translation: AAC50540.1.
AF545435 Genomic DNA. Translation: AAN16399.1.
AC078819 Genomic DNA. No translation available.
BC037557 mRNA. Translation: AAH37557.1.
CCDSCCDS9095.1.
RefSeqNP_003202.3. NM_003211.4.
UniGeneHs.584809.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1WYWX-ray2.10A112-339[»]
2D07X-ray2.10A112-339[»]
2RBAX-ray2.79A/B111-308[»]
3UFJX-ray2.97A/B111-308[»]
3UO7X-ray3.00A/B111-308[»]
3UOBX-ray3.01A/B111-308[»]
4FNCX-ray2.49A111-308[»]
4JGCX-ray2.58A111-308[»]
DisProtDP00719.
ProteinModelPortalQ13569.
SMRQ13569. Positions 117-332.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid112855. 26 interactions.
DIPDIP-32709N.
IntActQ13569. 10 interactions.
MINTMINT-1182514.
STRING9606.ENSP00000376611.

PTM databases

PhosphoSiteQ13569.

Polymorphism databases

DMDM46397791.

Proteomic databases

MaxQBQ13569.
PaxDbQ13569.
PRIDEQ13569.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000392872; ENSP00000376611; ENSG00000139372.
GeneID6996.
KEGGhsa:6996.
UCSCuc001tkg.3. human.

Organism-specific databases

CTD6996.
GeneCardsGC12P104359.
H-InvDBHIX0026376.
HGNCHGNC:11700. TDG.
HPAHPA052263.
MIM601423. gene.
neXtProtNX_Q13569.
PharmGKBPA36419.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG3663.
HOGENOMHOG000220820.
HOVERGENHBG003685.
InParanoidQ13569.
KOK03649.
OMANGQWMTQ.
OrthoDBEOG790G1Z.
PhylomeDBQ13569.
TreeFamTF328764.

Enzyme and pathway databases

ReactomeREACT_216. DNA Repair.
REACT_71. Gene Expression.

Gene expression databases

ArrayExpressQ13569.
BgeeQ13569.
CleanExHS_TDG.
GenevestigatorQ13569.

Family and domain databases

Gene3D3.40.470.10. 1 hit.
InterProIPR015637. DNA_glycosylase_G/T-mismatch.
IPR003310. Thymine-DNA_glycosylase.
IPR005122. Uracil-DNA_glycosylase-like.
[Graphical view]
PANTHERPTHR12159. PTHR12159. 1 hit.
PfamPF03167. UDG. 1 hit.
[Graphical view]
SMARTSM00986. UDG. 1 hit.
[Graphical view]
SUPFAMSSF52141. SSF52141. 1 hit.
TIGRFAMsTIGR00584. mug. 1 hit.
ProtoNetSearch...

Other

EvolutionaryTraceQ13569.
GeneWikiThymine-DNA_glycosylase.
GenomeRNAi6996.
NextBio27327.
PROQ13569.
SOURCESearch...

Entry information

Entry nameTDG_HUMAN
AccessionPrimary (citable) accession number: Q13569
Secondary accession number(s): Q8IUZ6, Q8IZM3
Entry history
Integrated into UniProtKB/Swiss-Prot: December 15, 1998
Last sequence update: April 13, 2004
Last modified: July 9, 2014
This is version 125 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 12

Human chromosome 12: entries, gene names and cross-references to MIM