TYDP2_DANRE
ID TYDP2_DANRE Reviewed; 369 AA.
AC Q5XJA0; A0SKZ8; A4FUK7; Q1LU95; Q1LWU3; Q4V912;
DT 07-JUN-2005, integrated into UniProtKB/Swiss-Prot.
DT 10-FEB-2009, sequence version 3.
DT 03-AUG-2022, entry version 107.
DE RecName: Full=Tyrosyl-DNA phosphodiesterase 2;
DE Short=Tyr-DNA phosphodiesterase 2;
DE EC=3.1.4.- {ECO:0000250|UniProtKB:Q9JJX7};
DE AltName: Full=5'-tyrosyl-DNA phosphodiesterase;
DE Short=5'-Tyr-DNA phosphodiesterase;
DE AltName: Full=TRAF and TNF receptor-associated protein homolog;
GN Name=tdp2; Synonyms=ttrap, ttrapl;
GN ORFNames=si:ch211-81e5.5, si:dkey-218n20.5;
OS Danio rerio (Zebrafish) (Brachydanio rerio).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Actinopterygii; Neopterygii; Teleostei; Ostariophysi; Cypriniformes;
OC Danionidae; Danioninae; Danio.
OX NCBI_TaxID=7955;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, AND DEVELOPMENTAL
RP STAGE.
RC TISSUE=Embryo;
RX PubMed=18039968; DOI=10.1242/dev.000026;
RA Esguerra C.V., Nelles L., Vermeire L., Ibrahimi A., Crawford A.D.,
RA Derua R., Janssens E., Waelkens E., Carmeliet P., Collen D.,
RA Huylebroeck D.;
RT "Ttrap is an essential modulator of Smad3-dependent Nodal signaling during
RT zebrafish gastrulation and left-right axis determination.";
RL Development 134:4381-4393(2007).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Tuebingen;
RX PubMed=23594743; DOI=10.1038/nature12111;
RA Howe K., Clark M.D., Torroja C.F., Torrance J., Berthelot C., Muffato M.,
RA Collins J.E., Humphray S., McLaren K., Matthews L., McLaren S., Sealy I.,
RA Caccamo M., Churcher C., Scott C., Barrett J.C., Koch R., Rauch G.J.,
RA White S., Chow W., Kilian B., Quintais L.T., Guerra-Assuncao J.A., Zhou Y.,
RA Gu Y., Yen J., Vogel J.H., Eyre T., Redmond S., Banerjee R., Chi J., Fu B.,
RA Langley E., Maguire S.F., Laird G.K., Lloyd D., Kenyon E., Donaldson S.,
RA Sehra H., Almeida-King J., Loveland J., Trevanion S., Jones M., Quail M.,
RA Willey D., Hunt A., Burton J., Sims S., McLay K., Plumb B., Davis J.,
RA Clee C., Oliver K., Clark R., Riddle C., Elliot D., Threadgold G.,
RA Harden G., Ware D., Begum S., Mortimore B., Kerry G., Heath P.,
RA Phillimore B., Tracey A., Corby N., Dunn M., Johnson C., Wood J., Clark S.,
RA Pelan S., Griffiths G., Smith M., Glithero R., Howden P., Barker N.,
RA Lloyd C., Stevens C., Harley J., Holt K., Panagiotidis G., Lovell J.,
RA Beasley H., Henderson C., Gordon D., Auger K., Wright D., Collins J.,
RA Raisen C., Dyer L., Leung K., Robertson L., Ambridge K., Leongamornlert D.,
RA McGuire S., Gilderthorp R., Griffiths C., Manthravadi D., Nichol S.,
RA Barker G., Whitehead S., Kay M., Brown J., Murnane C., Gray E.,
RA Humphries M., Sycamore N., Barker D., Saunders D., Wallis J., Babbage A.,
RA Hammond S., Mashreghi-Mohammadi M., Barr L., Martin S., Wray P.,
RA Ellington A., Matthews N., Ellwood M., Woodmansey R., Clark G., Cooper J.,
RA Tromans A., Grafham D., Skuce C., Pandian R., Andrews R., Harrison E.,
RA Kimberley A., Garnett J., Fosker N., Hall R., Garner P., Kelly D., Bird C.,
RA Palmer S., Gehring I., Berger A., Dooley C.M., Ersan-Urun Z., Eser C.,
RA Geiger H., Geisler M., Karotki L., Kirn A., Konantz J., Konantz M.,
RA Oberlander M., Rudolph-Geiger S., Teucke M., Lanz C., Raddatz G.,
RA Osoegawa K., Zhu B., Rapp A., Widaa S., Langford C., Yang F.,
RA Schuster S.C., Carter N.P., Harrow J., Ning Z., Herrero J., Searle S.M.,
RA Enright A., Geisler R., Plasterk R.H., Lee C., Westerfield M.,
RA de Jong P.J., Zon L.I., Postlethwait J.H., Nusslein-Volhard C.,
RA Hubbard T.J., Roest Crollius H., Rogers J., Stemple D.L.;
RT "The zebrafish reference genome sequence and its relationship to the human
RT genome.";
RL Nature 496:498-503(2013).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Embryo, and Ovary;
RG NIH - Zebrafish Gene Collection (ZGC) project;
RL Submitted (APR-2006) to the EMBL/GenBank/DDBJ databases.
RN [4] {ECO:0007744|PDB:4F1H, ECO:0007744|PDB:4FPV}
RP X-RAY CRYSTALLOGRAPHY (1.66 ANGSTROMS) OF 120-369 IN COMPLEX WITH MAGNESIUM
RP AND DNA, AND COFACTOR.
RX PubMed=23104058; DOI=10.1038/nsmb.2423;
RA Shi K., Kurahashi K., Gao R., Tsutakawa S.E., Tainer J.A., Pommier Y.,
RA Aihara H.;
RT "Structural basis for recognition of 5'-phosphotyrosine adducts by Tdp2.";
RL Nat. Struct. Mol. Biol. 19:1372-1377(2012).
RN [5] {ECO:0007744|PDB:6CA4}
RP X-RAY CRYSTALLOGRAPHY (1.62 ANGSTROMS) OF 121-369.
RX PubMed=29574079; DOI=10.1016/j.ejps.2018.03.021;
RA Ribeiro C.J.A., Kankanala J., Shi K., Kurahashi K., Kiselev E., Ravji A.,
RA Pommier Y., Aihara H., Wang Z.;
RT "New fluorescence-based high-throughput screening assay for small molecule
RT inhibitors of tyrosyl-DNA phosphodiesterase 2 (TDP2).";
RL Eur. J. Pharm. Sci. 118:67-79(2018).
CC -!- FUNCTION: DNA repair enzyme that can remove a variety of covalent
CC adducts from DNA through hydrolysis of a 5'-phosphodiester bond, giving
CC rise to DNA with a free 5' phosphate. Catalyzes the hydrolysis of dead-
CC end complexes between DNA and the topoisomerase 2 (top2) active site
CC tyrosine residue. Hydrolyzes 5'-phosphoglycolates on protruding 5' ends
CC on DNA double-strand breaks (DSBs) due to DNA damage by radiation and
CC free radicals (By similarity). Controls gastrulation movements and
CC left/right (L/R) axis determination via smad3-mediated regulation of
CC cdh1/e-cadherin. Regulates the formation of Kupffer's vesicle, a
CC signaling center essential for establishing L/R asymmetry. Modulates
CC smad3 activity through modulating nodal-acvr1/akt4 signaling.
CC {ECO:0000250|UniProtKB:Q9JJX7, ECO:0000269|PubMed:18039968}.
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:23104058};
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000250|UniProtKB:Q9JJX7};
CC Note=Binds 1 magnesium or manganese ion per subunit.
CC {ECO:0000269|PubMed:23104058};
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:O95551}. Nucleus,
CC PML body {ECO:0000250|UniProtKB:O95551}.
CC -!- TISSUE SPECIFICITY: Expressed ubiquitously during blastula stages and
CC throughout gastrulation. Shortly after shield formation, expressed
CC weakly in dorsal forerunner cells (DFCs). Between somite stages 5 and
CC 9, expressed in the tailbud and around the Kupffer's vesicle at a
CC higher level than the more uniform expression in the embryo.
CC {ECO:0000269|PubMed:18039968}.
CC -!- DEVELOPMENTAL STAGE: Expressed both maternally and zygotically.
CC {ECO:0000269|PubMed:18039968}.
CC -!- SIMILARITY: Belongs to the CCR4/nocturin family. TTRAP/TDP2 subfamily.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH83404.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=AAH97117.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAH97117.1; Type=Frameshift; Evidence={ECO:0000305};
CC Sequence=CAK05007.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
CC Sequence=CAK05424.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR EMBL; DQ524846; ABF70183.1; -; mRNA.
DR EMBL; BX511258; CAK05007.1; ALT_SEQ; Genomic_DNA.
DR EMBL; BX957279; CAK05424.1; ALT_SEQ; Genomic_DNA.
DR EMBL; BC083404; AAH83404.1; ALT_INIT; mRNA.
DR EMBL; BC097117; AAH97117.1; ALT_SEQ; mRNA.
DR EMBL; BC115076; AAI15077.1; -; mRNA.
DR RefSeq; NP_001073171.1; NM_001079703.1.
DR PDB; 4F1H; X-ray; 1.66 A; A=120-369, B=119-369.
DR PDB; 4FPV; X-ray; 1.73 A; A/B=113-369.
DR PDB; 6CA4; X-ray; 1.62 A; A/B/C=121-369.
DR PDBsum; 4F1H; -.
DR PDBsum; 4FPV; -.
DR PDBsum; 6CA4; -.
DR AlphaFoldDB; Q5XJA0; -.
DR SMR; Q5XJA0; -.
DR STRING; 7955.ENSDARP00000094388; -.
DR BindingDB; Q5XJA0; -.
DR ChEMBL; CHEMBL3813589; -.
DR PaxDb; Q5XJA0; -.
DR GeneID; 553516; -.
DR KEGG; dre:553516; -.
DR CTD; 553516; -.
DR ZFIN; ZDB-GENE-050816-1; tdp2b.
DR eggNOG; KOG2756; Eukaryota.
DR InParanoid; Q5XJA0; -.
DR OrthoDB; 1612152at2759; -.
DR PhylomeDB; Q5XJA0; -.
DR TreeFam; TF314813; -.
DR Reactome; R-DRE-5693571; Nonhomologous End-Joining (NHEJ).
DR PRO; PR:Q5XJA0; -.
DR Proteomes; UP000000437; Genome assembly.
DR Proteomes; UP000814640; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0016605; C:PML body; ISS:UniProtKB.
DR GO; GO:0070260; F:5'-tyrosyl-DNA phosphodiesterase activity; ISS:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IDA:ZFIN.
DR GO; GO:0000287; F:magnesium ion binding; ISS:UniProtKB.
DR GO; GO:0030145; F:manganese ion binding; ISS:UniProtKB.
DR GO; GO:0004518; F:nuclease activity; IEA:UniProtKB-KW.
DR GO; GO:0003697; F:single-stranded DNA binding; ISS:UniProtKB.
DR GO; GO:0070259; F:tyrosyl-DNA phosphodiesterase activity; IDA:ZFIN.
DR GO; GO:0060027; P:convergent extension involved in gastrulation; IMP:ZFIN.
DR GO; GO:0007368; P:determination of left/right symmetry; IMP:UniProtKB.
DR GO; GO:0006302; P:double-strand break repair; ISS:UniProtKB.
DR GO; GO:0007369; P:gastrulation; IMP:UniProtKB.
DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; IMP:ZFIN.
DR Gene3D; 3.60.10.10; -; 1.
DR InterPro; IPR036691; Endo/exonu/phosph_ase_sf.
DR InterPro; IPR005135; Endo/exonuclease/phosphatase.
DR InterPro; IPR009060; UBA-like_sf.
DR Pfam; PF03372; Exo_endo_phos; 1.
DR SUPFAM; SSF46934; SSF46934; 1.
DR SUPFAM; SSF56219; SSF56219; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Developmental protein; DNA damage; DNA repair; Hydrolase;
KW Magnesium; Metal-binding; Nuclease; Nucleus; Reference proteome.
FT CHAIN 1..369
FT /note="Tyrosyl-DNA phosphodiesterase 2"
FT /id="PRO_0000065677"
FT REGION 58..77
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 129..133
FT /note="Interaction with 5' end of substrate DNA"
FT /evidence="ECO:0000250|UniProtKB:Q9JJX7"
FT REGION 235..240
FT /note="Interaction with 5' end of substrate DNA"
FT /evidence="ECO:0000269|PubMed:23104058"
FT REGION 273..275
FT /note="Interaction with 5' end of substrate DNA"
FT /evidence="ECO:0000269|PubMed:23104058"
FT ACT_SITE 271
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250|UniProtKB:O95551"
FT BINDING 131
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:Q9JJX7"
FT BINDING 161
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000269|PubMed:23104058,
FT ECO:0007744|PDB:4FPV"
FT SITE 187
FT /note="Interaction with 5' end of substrate DNA"
FT /evidence="ECO:0000250|UniProtKB:Q9JJX7"
FT SITE 306
FT /note="Interaction with 5' end of substrate DNA"
FT /evidence="ECO:0000250|UniProtKB:Q9JJX7"
FT SITE 324
FT /note="Interaction with 5' end of substrate DNA"
FT /evidence="ECO:0000250|UniProtKB:Q9JJX7"
FT SITE 360
FT /note="Interaction with 5' end of substrate DNA"
FT /evidence="ECO:0000269|PubMed:23104058"
FT CONFLICT 5
FT /note="G -> E (in Ref. 1; ABF70183, 2; CAK05007 and 3;
FT AAH83404)"
FT /evidence="ECO:0000305"
FT CONFLICT 69
FT /note="D -> DVNSS (in Ref. 2; CAK05007)"
FT /evidence="ECO:0000305"
FT CONFLICT 140
FT /note="D -> E (in Ref. 2; CAK05007)"
FT /evidence="ECO:0000305"
FT CONFLICT 331
FT /note="S -> F (in Ref. 1; ABF70183)"
FT /evidence="ECO:0000305"
FT CONFLICT 335
FT /note="A -> G (in Ref. 3; AAH83404)"
FT /evidence="ECO:0000305"
FT CONFLICT 335
FT /note="A -> R (in Ref. 1; ABF70183 and 2; CAK05007)"
FT /evidence="ECO:0000305"
FT CONFLICT 337
FT /note="P -> A (in Ref. 1; ABF70183 and 2; CAK05007)"
FT /evidence="ECO:0000305"
FT CONFLICT 343
FT /note="M -> K (in Ref. 3; AAH97117)"
FT /evidence="ECO:0000305"
FT HELIX 115..119
FT /evidence="ECO:0007829|PDB:4FPV"
FT STRAND 123..129
FT /evidence="ECO:0007829|PDB:6CA4"
FT HELIX 138..152
FT /evidence="ECO:0007829|PDB:6CA4"
FT STRAND 155..162
FT /evidence="ECO:0007829|PDB:6CA4"
FT HELIX 164..173
FT /evidence="ECO:0007829|PDB:6CA4"
FT STRAND 177..182
FT /evidence="ECO:0007829|PDB:6CA4"
FT STRAND 184..194
FT /evidence="ECO:0007829|PDB:6CA4"
FT TURN 195..197
FT /evidence="ECO:0007829|PDB:6CA4"
FT STRAND 199..207
FT /evidence="ECO:0007829|PDB:6CA4"
FT STRAND 216..224
FT /evidence="ECO:0007829|PDB:6CA4"
FT STRAND 227..233
FT /evidence="ECO:0007829|PDB:6CA4"
FT HELIX 240..242
FT /evidence="ECO:0007829|PDB:6CA4"
FT HELIX 243..259
FT /evidence="ECO:0007829|PDB:6CA4"
FT STRAND 264..271
FT /evidence="ECO:0007829|PDB:6CA4"
FT HELIX 278..281
FT /evidence="ECO:0007829|PDB:6CA4"
FT STRAND 289..291
FT /evidence="ECO:0007829|PDB:6CA4"
FT HELIX 292..295
FT /evidence="ECO:0007829|PDB:6CA4"
FT HELIX 300..302
FT /evidence="ECO:0007829|PDB:6CA4"
FT STRAND 305..307
FT /evidence="ECO:0007829|PDB:6CA4"
FT TURN 308..310
FT /evidence="ECO:0007829|PDB:6CA4"
FT STRAND 325..330
FT /evidence="ECO:0007829|PDB:6CA4"
FT STRAND 339..346
FT /evidence="ECO:0007829|PDB:6CA4"
FT STRAND 362..368
FT /evidence="ECO:0007829|PDB:6CA4"
SQ SEQUENCE 369 AA; 41504 MW; FAC59FCCD675D667 CRC64;
MSALGESRTR LCDQFAFVSG SDSAVAQCYL AENEWDMERA LNSFFEAHMD SVFDEEAEKT
EVTGNKRKDD TAEASGTKKK LKTDNADCID LTAEEPTCSI TVNSKENQAE NGTAKSEVED
SKLSIISWNV DGLDTLNLAD RARGLCSYLA LYTPDVVFLQ ELIPAYVQYL KKRAVSYLFF
EGSDDGYFTG IMLRKSRVKF LESEIICFPT TQMMRNLLIA QVTFSGQKLY LMTSHLESCK
NQSQERTKQL RVVLQKIKEA PEDAIVIFAG DTNLRDAEVA NVGGLPAGVC DVWEQLGKQE
HCRYTWDTKA NSNKTVPYVS RCRFDRIFLR SAKTAPPVTP DHMALIGMEK LDCGRYTSDH
WGIYCTFNT
