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Protein

Tyrosyl-DNA phosphodiesterase 2

Gene

TDP2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 5'-phosphodiester bond, giving rise to DNA with a free 5' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase 2 (TOP2) active site tyrosine residue. Hydrolyzes 5'-phosphoglycolates on protruding 5' ends on DNA double-strand breaks (DSBs) due to DNA damage by radiation and free radicals. The 5'-tyrosyl DNA phosphodiesterase activity can enable the repair of TOP2-induced DSBs without the need for nuclease activity, creating a 'clean' DSB with 5'-phosphate termini that are ready for ligation. Has preference for single-stranded DNA or duplex DNA with a 4 base pair overhang as substrate. Has also 3'-tyrosyl DNA phosphodiesterase activity, but less efficiently and much slower than TDP1. Constitutes the major if not only 5'-tyrosyl-DNA phosphodiesterase in cells. Also acts as a 5'-tyrosyl-RNA phosphodiesterase following picornavirus infection: its activity is hijacked by picornavirus and acts by specifically cleaving the protein-RNA covalent linkage generated during the viral genomic RNA replication steps of a picornavirus infection, without impairing the integrity of viral RNA. Also acts as an adapter by participating in the specific activation of MAP3K7/TAK1 in response to TGF-beta: associates with components of the TGF-beta receptor-TRAF6-TAK1 signaling module and promotes their ubiquitination dependent complex formation. Involved in non-canonical TGF-beta induced signaling routes. May also act as a negative regulator of ETS1 and may inhibit NF-kappa-B activation. Acts as a regulator of ribosome biogenesis following stress.7 Publications

Cofactori

Mg2+3 Publications, Mn2+3 PublicationsNote: Magnesium. Can use other divalent cations as cofactor in vitro, such as manganese.3 Publications

Kineticsi

kcat is 3 sec(-1) with single-stranded 5'-tyrosyl DNA as substrate.

  1. KM=8 µM for single-stranded 5'-tyrosyl DNA1 Publication

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Metal bindingi120 – 1201MagnesiumCurated
    Metal bindingi152 – 1521MagnesiumBy similarity
    Metal bindingi262 – 2621MagnesiumCurated
    Metal bindingi264 – 2641MagnesiumBy similarity
    Metal bindingi350 – 3501MagnesiumBy similarity
    Active sitei351 – 3511Proton acceptorCurated
    Metal bindingi351 – 3511MagnesiumCurated

    GO - Molecular functioni

    • 5'-tyrosyl-DNA phosphodiesterase activity Source: UniProtKB
    • magnesium ion binding Source: UniProtKB
    • manganese ion binding Source: UniProtKB
    • nuclease activity Source: UniProtKB-KW
    • single-stranded DNA binding Source: UniProtKB
    • transcription corepressor activity Source: ProtInc
    • tyrosyl-RNA phosphodiesterase activity Source: UniProtKB

    GO - Biological processi

    • cell surface receptor signaling pathway Source: ProtInc
    • double-strand break repair Source: UniProtKB
    Complete GO annotation...

    Keywords - Molecular functioni

    Hydrolase, Nuclease

    Keywords - Biological processi

    DNA damage, DNA repair

    Keywords - Ligandi

    Magnesium, Metal-binding

    Enzyme and pathway databases

    ReactomeiR-HSA-5693571. Nonhomologous End-Joining (NHEJ).

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Tyrosyl-DNA phosphodiesterase 2 (EC:3.1.4.-)
    Short name:
    Tyr-DNA phosphodiesterase 2
    Short name:
    hTDP2
    Alternative name(s):
    5'-tyrosyl-DNA phosphodiesterase
    Short name:
    5'-Tyr-DNA phosphodiesterase
    ETS1-associated protein 2
    ETS1-associated protein II
    Short name:
    EAPII
    TRAF and TNF receptor-associated protein
    Tyrosyl-RNA phosphodiesterase
    VPg unlinkase
    Gene namesi
    Name:TDP2
    Synonyms:EAP2, TTRAP
    ORF Names:AD-022
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 6

    Organism-specific databases

    HGNCiHGNC:17768. TDP2.

    Subcellular locationi

    • Nucleus
    • NucleusPML body
    • Nucleusnucleolus
    • Cytoplasm

    • Note: Localizes to nucleolar cavities following stress; localization to nucleolus is dependent on PML protein. In case of infection by picornavirus, relocalizes to cytoplasmic sites distinct from those containing viral proteins associated with RNA replication or encapsidation.

    GO - Cellular componenti

    • cytoplasm Source: UniProtKB
    • intercellular bridge Source: HPA
    • nucleolus Source: UniProtKB-SubCell
    • nucleus Source: UniProtKB
    • PML body Source: UniProtKB
    Complete GO annotation...

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi88 – 881T → A: Abolishes function, but retains ability to interact with SMAD3; when associated with A-92. 1 Publication
    Mutagenesisi92 – 921T → A: Abolishes function, but retains ability to interact with SMAD3; when associated with A-88. 1 Publication
    Mutagenesisi120 – 1201N → A: Strongly reduced phosphodiesterase activity. 1 Publication
    Mutagenesisi152 – 1521E → A: Loss of phosphodiesterase activity. 2 Publications
    Mutagenesisi262 – 2621D → A: Loss of phosphodiesterase activity. 2 Publications
    Mutagenesisi351 – 3511H → A: Loss of phosphodiesterase activity. 1 Publication

    Organism-specific databases

    MalaCardsiTDP2.
    Orphaneti404493. Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to TUD deficiency.
    PharmGKBiPA165618310.

    Chemistry

    ChEMBLiCHEMBL2169736.

    Polymorphism and mutation databases

    BioMutaiTDP2.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 362362Tyrosyl-DNA phosphodiesterase 2PRO_0000065678Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei1 – 11N-acetylmethionineCombined sources
    Modified residuei88 – 881Phosphothreonine; by ACVR1B1 Publication
    Modified residuei92 – 921Phosphothreonine; by ACVR1B1 Publication
    Modified residuei95 – 951PhosphoserineCombined sources

    Post-translational modificationi

    Ubiquitinated by TRAF6.1 Publication

    Keywords - PTMi

    Acetylation, Phosphoprotein, Ubl conjugation

    Proteomic databases

    EPDiO95551.
    MaxQBiO95551.
    PaxDbiO95551.
    PeptideAtlasiO95551.
    PRIDEiO95551.

    PTM databases

    iPTMnetiO95551.
    PhosphoSiteiO95551.

    Expressioni

    Tissue specificityi

    Widely expressed.1 Publication

    Gene expression databases

    BgeeiENSG00000111802.
    CleanExiHS_TTRAP.
    ExpressionAtlasiO95551. baseline and differential.
    GenevisibleiO95551. HS.

    Organism-specific databases

    HPAiCAB073398.
    HPA054272.

    Interactioni

    Subunit structurei

    Interacts with TRAF2, TRAF3, TRAF5, TRAF6, TNFRSF8/CD30, TNFRSF5/CD40, TNFRSF1B/TNF-R75, ETS1, ETS2, FLI1, SMAD3 and ACVR1B/ALK4.3 Publications

    Protein-protein interaction databases

    BioGridi119615. 35 interactions.
    IntActiO95551. 22 interactions.
    MINTiMINT-5005899.
    STRINGi9606.ENSP00000367440.

    Chemistry

    BindingDBiO95551.

    Structurei

    Secondary structure

    1
    362
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi110 – 12011Combined sources
    Helixi129 – 14315Combined sources
    Beta strandi146 – 1538Combined sources
    Helixi155 – 16410Combined sources
    Beta strandi167 – 1737Combined sources
    Beta strandi175 – 18511Combined sources
    Turni186 – 1883Combined sources
    Beta strandi190 – 1989Combined sources
    Beta strandi207 – 2159Combined sources
    Beta strandi218 – 2247Combined sources
    Helixi231 – 2333Combined sources
    Helixi234 – 25017Combined sources
    Beta strandi255 – 2628Combined sources
    Helixi267 – 2726Combined sources
    Helixi283 – 2864Combined sources
    Beta strandi291 – 2944Combined sources
    Beta strandi296 – 2983Combined sources
    Turni299 – 3013Combined sources
    Beta strandi316 – 3216Combined sources
    Beta strandi328 – 33710Combined sources
    Beta strandi353 – 3608Combined sources

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    5INOX-ray3.21A/B108-362[»]
    5J3PX-ray3.10A/B113-362[»]
    5J3SX-ray3.40A113-362[»]
    ProteinModelPortaliO95551.
    SMRiO95551. Positions 31-362.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Sequence similaritiesi

    Belongs to the CCR4/nocturin family.Curated

    Phylogenomic databases

    eggNOGiKOG2756. Eukaryota.
    ENOG410XP85. LUCA.
    GeneTreeiENSGT00390000014242.
    HOVERGENiHBG079625.
    InParanoidiO95551.
    KOiK19619.
    OMAiQCFLAEN.
    OrthoDBiEOG091G0FBI.
    PhylomeDBiO95551.
    TreeFamiTF314813.

    Family and domain databases

    Gene3Di3.60.10.10. 1 hit.
    InterProiIPR005135. Endo/exonuclease/phosphatase.
    IPR009060. UBA-like.
    [Graphical view]
    PfamiPF03372. Exo_endo_phos. 1 hit.
    [Graphical view]
    SUPFAMiSSF46934. SSF46934. 1 hit.
    SSF56219. SSF56219. 1 hit.

    Sequences (3)i

    Sequence statusi: Complete.

    This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

    Isoform 1 (identifier: O95551-1) [UniParc]FASTAAdd to basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

            10         20         30         40         50
    MELGSCLEGG REAAEEEGEP EVKKRRLLCV EFASVASCDA AVAQCFLAEN
    60 70 80 90 100
    DWEMERALNS YFEPPVEESA LERRPETISE PKTYVDLTNE ETTDSTTSKI
    110 120 130 140 150
    SPSEDTQQEN GSMFSLITWN IDGLDLNNLS ERARGVCSYL ALYSPDVIFL
    160 170 180 190 200
    QEVIPPYYSY LKKRSSNYEI ITGHEEGYFT AIMLKKSRVK LKSQEIIPFP
    210 220 230 240 250
    STKMMRNLLC VHVNVSGNEL CLMTSHLEST RGHAAERMNQ LKMVLKKMQE
    260 270 280 290 300
    APESATVIFA GDTNLRDREV TRCGGLPNNI VDVWEFLGKP KHCQYTWDTQ
    310 320 330 340 350
    MNSNLGITAA CKLRFDRIFF RAAAEEGHII PRSLDLLGLE KLDCGRFPSD
    360
    HWGLLCNLDI IL
    Length:362
    Mass (Da):40,930
    Last modified:May 1, 1999 - v1
    Checksum:i37892E125DB64410
    GO
    Isoform 2 (identifier: O95551-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-1: M → MRERHDTGACAEPRVGLLFRLKGRCRGGRKM

    Note: No experimental confirmation available.
    Show »
    Length:392
    Mass (Da):44,339
    Checksum:i6B822134BDD395F3
    GO
    Isoform 3 (identifier: O95551-3) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         60-137: Missing.

    Note: No experimental confirmation available.
    Show »
    Length:284
    Mass (Da):32,176
    Checksum:i3FBF514CDDECB196
    GO

    Sequence cautioni

    The sequence BAG59230 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated
    The sequence CAD92510 differs from that shown. Reason: Erroneous gene model prediction. Curated

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti31 – 311E → R in AAF64144 (PubMed:10931946).Curated
    Sequence conflicti61 – 611Y → C in BAA92119 (PubMed:14702039).Curated
    Sequence conflicti72 – 721E → G in BAG60857 (PubMed:14702039).Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti166 – 1661S → G.
    Corresponds to variant rs35977478 [ dbSNP | Ensembl ].
    VAR_051464
    Natural varianti249 – 2491Q → E.1 Publication
    Corresponds to variant rs2294689 [ dbSNP | Ensembl ].
    VAR_022634
    Natural varianti268 – 2681R → Q.1 Publication
    Corresponds to variant rs17249952 [ dbSNP | Ensembl ].
    VAR_022635

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 11M → MRERHDTGACAEPRVGLLFR LKGRCRGGRKM in isoform 2. 1 PublicationVSP_038523
    Alternative sequencei60 – 13778Missing in isoform 3. 1 PublicationVSP_038524Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AJ269473 mRNA. Translation: CAB92966.1.
    AF201687 mRNA. Translation: AAG35600.1.
    AF223469 mRNA. Translation: AAF64144.1.
    AK002168 mRNA. Translation: BAA92119.1.
    AK296623 mRNA. Translation: BAG59230.1. Different initiation.
    AK298699 mRNA. Translation: BAG60857.1.
    AY613922 Genomic DNA. Translation: AAT09764.1.
    AL031775 Genomic DNA. Translation: CAA21141.1.
    AL031775 Genomic DNA. Translation: CAD92510.1. Sequence problems.
    BC017553 mRNA. Translation: AAH17553.1.
    BC110375 mRNA. Translation: AAI10376.1.
    CCDSiCCDS4557.1. [O95551-1]
    RefSeqiNP_057698.2. NM_016614.2. [O95551-1]
    UniGeneiHs.403010.

    Genome annotation databases

    EnsembliENST00000378198; ENSP00000367440; ENSG00000111802. [O95551-1]
    GeneIDi51567.
    KEGGihsa:51567.
    UCSCiuc003nej.4. human. [O95551-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Cross-referencesi

    Web resourcesi

    SeattleSNPs

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AJ269473 mRNA. Translation: CAB92966.1.
    AF201687 mRNA. Translation: AAG35600.1.
    AF223469 mRNA. Translation: AAF64144.1.
    AK002168 mRNA. Translation: BAA92119.1.
    AK296623 mRNA. Translation: BAG59230.1. Different initiation.
    AK298699 mRNA. Translation: BAG60857.1.
    AY613922 Genomic DNA. Translation: AAT09764.1.
    AL031775 Genomic DNA. Translation: CAA21141.1.
    AL031775 Genomic DNA. Translation: CAD92510.1. Sequence problems.
    BC017553 mRNA. Translation: AAH17553.1.
    BC110375 mRNA. Translation: AAI10376.1.
    CCDSiCCDS4557.1. [O95551-1]
    RefSeqiNP_057698.2. NM_016614.2. [O95551-1]
    UniGeneiHs.403010.

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    5INOX-ray3.21A/B108-362[»]
    5J3PX-ray3.10A/B113-362[»]
    5J3SX-ray3.40A113-362[»]
    ProteinModelPortaliO95551.
    SMRiO95551. Positions 31-362.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi119615. 35 interactions.
    IntActiO95551. 22 interactions.
    MINTiMINT-5005899.
    STRINGi9606.ENSP00000367440.

    Chemistry

    BindingDBiO95551.
    ChEMBLiCHEMBL2169736.

    PTM databases

    iPTMnetiO95551.
    PhosphoSiteiO95551.

    Polymorphism and mutation databases

    BioMutaiTDP2.

    Proteomic databases

    EPDiO95551.
    MaxQBiO95551.
    PaxDbiO95551.
    PeptideAtlasiO95551.
    PRIDEiO95551.

    Protocols and materials databases

    DNASUi51567.
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000378198; ENSP00000367440; ENSG00000111802. [O95551-1]
    GeneIDi51567.
    KEGGihsa:51567.
    UCSCiuc003nej.4. human. [O95551-1]

    Organism-specific databases

    CTDi51567.
    GeneCardsiTDP2.
    HGNCiHGNC:17768. TDP2.
    HPAiCAB073398.
    HPA054272.
    MalaCardsiTDP2.
    MIMi605764. gene.
    neXtProtiNX_O95551.
    Orphaneti404493. Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to TUD deficiency.
    PharmGKBiPA165618310.
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiKOG2756. Eukaryota.
    ENOG410XP85. LUCA.
    GeneTreeiENSGT00390000014242.
    HOVERGENiHBG079625.
    InParanoidiO95551.
    KOiK19619.
    OMAiQCFLAEN.
    OrthoDBiEOG091G0FBI.
    PhylomeDBiO95551.
    TreeFamiTF314813.

    Enzyme and pathway databases

    ReactomeiR-HSA-5693571. Nonhomologous End-Joining (NHEJ).

    Miscellaneous databases

    ChiTaRSiTDP2. human.
    GeneWikiiTTRAP.
    GenomeRNAii51567.
    PROiO95551.
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000111802.
    CleanExiHS_TTRAP.
    ExpressionAtlasiO95551. baseline and differential.
    GenevisibleiO95551. HS.

    Family and domain databases

    Gene3Di3.60.10.10. 1 hit.
    InterProiIPR005135. Endo/exonuclease/phosphatase.
    IPR009060. UBA-like.
    [Graphical view]
    PfamiPF03372. Exo_endo_phos. 1 hit.
    [Graphical view]
    SUPFAMiSSF46934. SSF46934. 1 hit.
    SSF56219. SSF56219. 1 hit.
    ProtoNetiSearch...

    Entry informationi

    Entry nameiTYDP2_HUMAN
    AccessioniPrimary (citable) accession number: O95551
    Secondary accession number(s): B4DKL8
    , B4DQ95, Q2TBE2, Q5JYM0, Q7Z6U5, Q9NUK5, Q9NYY9
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: June 7, 2005
    Last sequence update: May 1, 1999
    Last modified: September 7, 2016
    This is version 136 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (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.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 6
      Human chromosome 6: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. SIMILARITY comments
      Index of protein domains and families

    Similar proteinsi

    Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
    100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
    90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
    50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.