TYDP1_HUMAN
ID TYDP1_HUMAN Reviewed; 608 AA.
AC Q9NUW8; Q2HXX4; Q86TV8; Q96BK7; Q9NZM7; Q9NZM8;
DT 24-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 24-OCT-2003, sequence version 2.
DT 03-AUG-2022, entry version 174.
DE RecName: Full=Tyrosyl-DNA phosphodiesterase 1;
DE Short=Tyr-DNA phosphodiesterase 1;
DE EC=3.1.4.- {ECO:0000269|PubMed:15111055, ECO:0000269|PubMed:16141202, ECO:0000269|PubMed:22822062};
GN Name=TDP1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Placenta;
RA Li W.B., Gruber C., Jessee J., Polayes D.;
RT "Full-length cDNA libraries and normalization.";
RL Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ASP-95; LEU-101; THR-134;
RP GLY-187; GLN-304 AND ALA-569.
RG NIEHS SNPs program;
RL Submitted (JAN-2006) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12508121; DOI=10.1038/nature01348;
RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H.,
RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T.,
RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B.,
RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D.,
RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R.,
RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S.,
RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C.,
RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S.,
RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C.,
RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P.,
RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J.,
RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F.,
RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F.,
RA Waterston R., Hood L., Weissenbach J.;
RT "The DNA sequence and analysis of human chromosome 14.";
RL Nature 421:601-607(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Pancreas;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 6-608 (ISOFORM 1).
RX PubMed=10521354; DOI=10.1126/science.286.5439.552;
RA Pouliot J.J., Yao K.C., Robertson C.A., Nash H.A.;
RT "Yeast gene for a Tyr-DNA phosphodiesterase that repairs topoisomerase I
RT complexes.";
RL Science 286:552-555(1999).
RN [7]
RP SIMILARITY TO PHOSPHOLIPASE D SUPERFAMILY, AND MUTAGENESIS OF HIS-263;
RP LYS-265; HIS-493 AND LYS-495.
RX PubMed=11572945; DOI=10.1073/pnas.211429198;
RA Interthal H., Pouliot J.J., Champoux J.J.;
RT "The tyrosyl-DNA phosphodiesterase Tdp1 is a member of the phospholipase D
RT superfamily.";
RL Proc. Natl. Acad. Sci. U.S.A. 98:12009-12014(2001).
RN [8]
RP FUNCTION.
RX PubMed=12023295; DOI=10.1074/jbc.m204688200;
RA Inamdar K.V., Pouliot J.J., Zhou T., Lees-Miller S.P., Rasouli-Nia A.,
RA Povirk L.F.;
RT "Conversion of phosphoglycolate to phosphate termini on 3' overhangs of DNA
RT double strand breaks by the human tyrosyl-DNA phosphodiesterase hTdp1.";
RL J. Biol. Chem. 277:27162-27168(2002).
RN [9]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, ENZYME MECHANISM, AND
RP MUTAGENESIS OF HIS-263; LYS-265; ASN-283; GLN-294; HIS-493; LYS-495;
RP ASN-516 AND GLU-538.
RX PubMed=15111055; DOI=10.1016/j.jmb.2004.03.013;
RA Raymond A.C., Rideout M.C., Staker B., Hjerrild K., Burgin A.B. Jr.;
RT "Analysis of human tyrosyl-DNA phosphodiesterase I catalytic residues.";
RL J. Mol. Biol. 338:895-906(2004).
RN [10]
RP FUNCTION.
RX PubMed=15811850; DOI=10.1074/jbc.m502148200;
RA Raymond A.C., Staker B.L., Burgin A.B. Jr.;
RT "Substrate specificity of tyrosyl-DNA phosphodiesterase I (Tdp1).";
RL J. Biol. Chem. 280:22029-22035(2005).
RN [11]
RP FUNCTION, CATALYTIC ACTIVITY, AND CHARACTERIZATION OF VARIANT SCAN1
RP ARG-493.
RX PubMed=16141202; DOI=10.1074/jbc.m508898200;
RA Interthal H., Chen H.J., Champoux J.J.;
RT "Human Tdp1 cleaves a broad spectrum of substrates, including phosphoamide
RT linkages.";
RL J. Biol. Chem. 280:36518-36528(2005).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-61, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-147 AND SER-148, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [16]
RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=22822062; DOI=10.1074/jbc.m112.393983;
RA Gao R., Huang S.Y., Marchand C., Pommier Y.;
RT "Biochemical characterization of human Tyrosyl DNA Phosphodiesterase 2
RT (TDP2/TTRAP): a Mg2+/Mn2+-dependent phosphodiesterase specific for the
RT repair of topoisomerase cleavage complexes.";
RL J. Biol. Chem. 287:30842-30852(2012).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-61, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 149-608 IN COMPLEXES WITH
RP SUBSTRATE; VANADATE AND TUNGSTATE, AND ACTIVE SITE.
RX PubMed=12470949; DOI=10.1016/s0022-2836(02)01154-3;
RA Davies D.R., Interthal H., Champoux J.J., Hol W.G.J.;
RT "Insights into substrate binding and catalytic mechanism of human tyrosyl-
RT DNA phosphodiesterase (Tdp1) from vanadate and tungstate-inhibited
RT structures.";
RL J. Mol. Biol. 324:917-932(2002).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (1.69 ANGSTROMS) OF 149-608, AND SUBUNIT.
RX PubMed=11839309; DOI=10.1016/s0969-2126(02)00707-4;
RA Davies D.R., Interthal H., Champoux J.J., Hol W.G.J.;
RT "The crystal structure of human tyrosyl-DNA phosphodiesterase, Tdp1.";
RL Structure 10:237-248(2002).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.03 ANGSTROMS) OF 149-608.
RX PubMed=12618186; DOI=10.1016/s1074-5521(03)00021-8;
RA Davies D.R., Interthal H., Champoux J.J., Hol W.G.J.;
RT "Crystal structure of a transition state mimic for TDP1 assembled from
RT vanadate, DNA, and a topoisomerase I-derived peptide.";
RL Chem. Biol. 10:139-147(2003).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 149-608 IN COMPLEXES WITH
RP SUBSTRATES.
RX PubMed=14761185; DOI=10.1021/jm030487x;
RA Davies D.R., Interthal H., Champoux J.J., Hol W.G.J.;
RT "Explorations of peptide and oligonucleotide binding sites of tyrosyl-DNA
RT phosphodiesterase using vanadate complexes.";
RL J. Med. Chem. 47:829-837(2004).
RN [22]
RP VARIANT SCAN1 ARG-493, VARIANT LEU-566, AND TISSUE SPECIFICITY.
RX PubMed=12244316; DOI=10.1038/ng987;
RA Takashima H., Boerkoel C.F., John J., Saifi G.M., Salih M.A.M.,
RA Armstrong D., Mao Y., Quiocho F.A., Roa B.B., Nakagawa M., Stockton D.W.,
RA Lupski J.R.;
RT "Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair
RT enzyme, in spinocerebellar ataxia with axonal neuropathy.";
RL Nat. Genet. 32:267-272(2002).
RN [23]
RP CHARACTERIZATION OF VARIANT SCAN1 ARG-493, SUBCELLULAR LOCATION, AND
RP PHOSPHORYLATION.
RX PubMed=15647511; DOI=10.1093/nar/gki170;
RA Zhou T., Lee J.W., Tatavarthi H., Lupski J.R., Valerie K., Povirk L.F.;
RT "Deficiency in 3'-phosphoglycolate processing in human cells with a
RT hereditary mutation in tyrosyl-DNA phosphodiesterase (TDP1).";
RL Nucleic Acids Res. 33:289-297(2005).
RN [24]
RP CHARACTERIZATION OF VARIANT SCAN1 ARG-493.
RX PubMed=15920477; DOI=10.1038/sj.emboj.7600694;
RA Interthal H., Chen H.J., Kehl-Fie T.E., Zotzmann J., Leppard J.B.,
RA Champoux J.J.;
RT "SCAN1 mutant Tdp1 accumulates the enzyme-DNA intermediate and causes
RT camptothecin hypersensitivity.";
RL EMBO J. 24:2224-2233(2005).
RN [25]
RP CHARACTERIZATION OF VARIANT SCAN1 ARG-493, AND TISSUE SPECIFICITY.
RX PubMed=17948061; DOI=10.1038/sj.emboj.7601885;
RA Hirano R., Interthal H., Huang C., Nakamura T., Deguchi K., Choi K.,
RA Bhattacharjee M.B., Arimura K., Umehara F., Izumo S., Northrop J.L.,
RA Salih M.A.M., Inoue K., Armstrong D.L., Champoux J.J., Takashima H.,
RA Boerkoel C.F.;
RT "Spinocerebellar ataxia with axonal neuropathy: consequence of a Tdp1
RT recessive neomorphic mutation?";
RL EMBO J. 26:4732-4743(2007).
CC -!- FUNCTION: DNA repair enzyme that can remove a variety of covalent
CC adducts from DNA through hydrolysis of a 3'-phosphodiester bond, giving
CC rise to DNA with a free 3' phosphate. Catalyzes the hydrolysis of dead-
CC end complexes between DNA and the topoisomerase I active site tyrosine
CC residue. Hydrolyzes 3'-phosphoglycolates on protruding 3' ends on DNA
CC double-strand breaks due to DNA damage by radiation and free radicals.
CC Acts on blunt-ended double-strand DNA breaks and on single-stranded
CC DNA. Has low 3'exonuclease activity and can remove a single nucleoside
CC from the 3'end of DNA and RNA molecules with 3'hydroxyl groups. Has no
CC exonuclease activity towards DNA or RNA with a 3'phosphate.
CC {ECO:0000269|PubMed:12023295, ECO:0000269|PubMed:15111055,
CC ECO:0000269|PubMed:15811850, ECO:0000269|PubMed:16141202,
CC ECO:0000269|PubMed:22822062}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.08 uM for 14-mer single-stranded oligo with a 3'-phosphotyrosine
CC {ECO:0000269|PubMed:22822062};
CC Note=kcat is 7 sec(-1) with single-stranded 5'-tyrosyl DNA as
CC substrate.;
CC -!- SUBUNIT: Monomer. {ECO:0000269|PubMed:11839309}.
CC -!- INTERACTION:
CC Q9NUW8; P46379-2: BAG6; NbExp=3; IntAct=EBI-2902553, EBI-10988864;
CC Q9NUW8; Q9H816: DCLRE1B; NbExp=3; IntAct=EBI-2902553, EBI-3508943;
CC Q9NUW8; Q9BYZ2: LDHAL6B; NbExp=3; IntAct=EBI-2902553, EBI-1108377;
CC Q9NUW8; A4FUJ8: MKL1; NbExp=3; IntAct=EBI-2902553, EBI-21250407;
CC Q9NUW8; O75925: PIAS1; NbExp=3; IntAct=EBI-2902553, EBI-629434;
CC Q9NUW8; Q9NS23-4: RASSF1; NbExp=3; IntAct=EBI-2902553, EBI-438710;
CC Q9NUW8; Q6ZNA4-2: RNF111; NbExp=3; IntAct=EBI-2902553, EBI-21535400;
CC Q9NUW8; Q8N488: RYBP; NbExp=3; IntAct=EBI-2902553, EBI-752324;
CC Q9NUW8; Q8IUW3: SPATA2L; NbExp=3; IntAct=EBI-2902553, EBI-2510414;
CC Q9NUW8; Q15554-4: TERF2; NbExp=3; IntAct=EBI-2902553, EBI-25840535;
CC Q9NUW8; Q08AM6: VAC14; NbExp=3; IntAct=EBI-2902553, EBI-2107455;
CC Q9NUW8; P18887: XRCC1; NbExp=2; IntAct=EBI-2902553, EBI-947466;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:15647511}. Cytoplasm
CC {ECO:0000269|PubMed:15647511}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9NUW8-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9NUW8-2; Sequence=VSP_055765, VSP_055766;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. Similar expression
CC throughout the central nervous system (whole brain, amygdala, caudate
CC nucleus, cerebellum, cerebral cortex, frontal lobe, hippocampus,
CC medulla oblongata, occipital lobe, putamen, substantia nigra, temporal
CC lobe, thalamus, nucleus accumbens and spinal cord) and increased
CC expression in testis and thymus. {ECO:0000269|PubMed:12244316,
CC ECO:0000269|PubMed:17948061}.
CC -!- PTM: Phosphorylated on serine and/or threonine residues, but not on
CC tyrosine residues. {ECO:0000269|PubMed:15647511}.
CC -!- DISEASE: Spinocerebellar ataxia, autosomal recessive, with axonal
CC neuropathy 1 (SCAN1) [MIM:607250]: A form of spinocerebellar ataxia, a
CC clinically and genetically heterogeneous group of cerebellar disorders.
CC Patients show progressive incoordination of gait and often poor
CC coordination of hands, speech and eye movements, due to degeneration of
CC the cerebellum with variable involvement of the brainstem and spinal
CC cord. SCAN1 is an autosomal recessive cerebellar ataxia (ARCA)
CC associated with peripheral axonal motor and sensory neuropathy, distal
CC muscular atrophy, pes cavus and steppage gait as seen in Charcot-Marie-
CC Tooth neuropathy. All affected individuals have normal intelligence.
CC {ECO:0000269|PubMed:12244316, ECO:0000269|PubMed:15647511,
CC ECO:0000269|PubMed:15920477, ECO:0000269|PubMed:16141202,
CC ECO:0000269|PubMed:17948061}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the tyrosyl-DNA phosphodiesterase family.
CC {ECO:0000305}.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/tdp1/";
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DR EMBL; BX161451; CAD61915.1; -; mRNA.
DR EMBL; AK001952; BAA91997.1; -; mRNA.
DR EMBL; DQ367843; ABC79301.1; -; Genomic_DNA.
DR EMBL; AL137128; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC015474; AAH15474.1; -; mRNA.
DR EMBL; AF182002; AAF65623.1; -; mRNA.
DR EMBL; AF182003; AAF65624.1; -; mRNA.
DR CCDS; CCDS9888.1; -. [Q9NUW8-1]
DR RefSeq; NP_001008744.1; NM_001008744.1. [Q9NUW8-1]
DR RefSeq; NP_060789.2; NM_018319.3. [Q9NUW8-1]
DR RefSeq; XP_005267904.1; XM_005267847.2.
DR RefSeq; XP_005267905.1; XM_005267848.2. [Q9NUW8-1]
DR RefSeq; XP_006720260.1; XM_006720197.3. [Q9NUW8-1]
DR RefSeq; XP_006720261.1; XM_006720198.3.
DR RefSeq; XP_011535244.1; XM_011536942.2. [Q9NUW8-1]
DR RefSeq; XP_011535245.1; XM_011536943.2.
DR RefSeq; XP_016876928.1; XM_017021439.1. [Q9NUW8-1]
DR RefSeq; XP_016876931.1; XM_017021442.1.
DR RefSeq; XP_016876932.1; XM_017021443.1.
DR RefSeq; XP_016876933.1; XM_017021444.1.
DR PDB; 1JY1; X-ray; 1.69 A; A=149-608.
DR PDB; 1MU7; X-ray; 2.00 A; A/B=149-608.
DR PDB; 1MU9; X-ray; 2.05 A; A/B=149-608.
DR PDB; 1NOP; X-ray; 2.30 A; A/B=149-608.
DR PDB; 1QZQ; X-ray; 2.40 A; A/B=149-608.
DR PDB; 1RFF; X-ray; 1.70 A; A/B=149-608.
DR PDB; 1RFI; X-ray; 2.20 A; A/B=149-608.
DR PDB; 1RG1; X-ray; 2.10 A; A/B=149-608.
DR PDB; 1RG2; X-ray; 2.10 A; A/B=149-608.
DR PDB; 1RGT; X-ray; 2.00 A; A/B=149-608.
DR PDB; 1RGU; X-ray; 2.22 A; A/B=149-608.
DR PDB; 1RH0; X-ray; 2.30 A; A/B=149-608.
DR PDB; 5NW9; X-ray; 2.04 A; A/B=149-608.
DR PDB; 5NWA; X-ray; 3.20 A; A/B=149-608.
DR PDB; 6DHU; X-ray; 1.63 A; A/B=148-608.
DR PDB; 6DIE; X-ray; 1.78 A; A/B=148-608.
DR PDB; 6DIH; X-ray; 1.78 A; A/B=148-608.
DR PDB; 6DIM; X-ray; 1.81 A; A/B=148-608.
DR PDB; 6DJD; X-ray; 1.78 A; A/B=148-608.
DR PDB; 6DJE; X-ray; 1.71 A; A/B=148-608.
DR PDB; 6DJF; X-ray; 1.67 A; A/B=148-608.
DR PDB; 6DJG; X-ray; 1.88 A; A/B=148-608.
DR PDB; 6DJH; X-ray; 1.92 A; A/B=148-608.
DR PDB; 6DJI; X-ray; 1.75 A; A/B=148-608.
DR PDB; 6DJJ; X-ray; 1.74 A; A/B=148-608.
DR PDB; 6MJ5; X-ray; 1.85 A; A/B=149-608.
DR PDB; 6MYZ; X-ray; 1.66 A; A/B=148-608.
DR PDB; 6MZ0; X-ray; 1.97 A; A/B=148-608.
DR PDB; 6N0D; X-ray; 1.45 A; A/B=148-608.
DR PDB; 6N0N; X-ray; 1.48 A; A/B=148-608.
DR PDB; 6N0O; X-ray; 1.94 A; A/B=148-608.
DR PDB; 6N0R; X-ray; 1.54 A; A/B=148-608.
DR PDB; 6N17; X-ray; 1.64 A; A/B=148-608.
DR PDB; 6N19; X-ray; 1.50 A; A/B=148-608.
DR PDB; 6W4R; X-ray; 1.82 A; A/B=148-608.
DR PDB; 6W7J; X-ray; 1.49 A; A/B=148-608.
DR PDB; 6W7K; X-ray; 1.70 A; A/B=148-608.
DR PDB; 6W7L; X-ray; 1.86 A; A/B=148-608.
DR PDBsum; 1JY1; -.
DR PDBsum; 1MU7; -.
DR PDBsum; 1MU9; -.
DR PDBsum; 1NOP; -.
DR PDBsum; 1QZQ; -.
DR PDBsum; 1RFF; -.
DR PDBsum; 1RFI; -.
DR PDBsum; 1RG1; -.
DR PDBsum; 1RG2; -.
DR PDBsum; 1RGT; -.
DR PDBsum; 1RGU; -.
DR PDBsum; 1RH0; -.
DR PDBsum; 5NW9; -.
DR PDBsum; 5NWA; -.
DR PDBsum; 6DHU; -.
DR PDBsum; 6DIE; -.
DR PDBsum; 6DIH; -.
DR PDBsum; 6DIM; -.
DR PDBsum; 6DJD; -.
DR PDBsum; 6DJE; -.
DR PDBsum; 6DJF; -.
DR PDBsum; 6DJG; -.
DR PDBsum; 6DJH; -.
DR PDBsum; 6DJI; -.
DR PDBsum; 6DJJ; -.
DR PDBsum; 6MJ5; -.
DR PDBsum; 6MYZ; -.
DR PDBsum; 6MZ0; -.
DR PDBsum; 6N0D; -.
DR PDBsum; 6N0N; -.
DR PDBsum; 6N0O; -.
DR PDBsum; 6N0R; -.
DR PDBsum; 6N17; -.
DR PDBsum; 6N19; -.
DR PDBsum; 6W4R; -.
DR PDBsum; 6W7J; -.
DR PDBsum; 6W7K; -.
DR PDBsum; 6W7L; -.
DR AlphaFoldDB; Q9NUW8; -.
DR SASBDB; Q9NUW8; -.
DR SMR; Q9NUW8; -.
DR BioGRID; 120890; 24.
DR CORUM; Q9NUW8; -.
DR IntAct; Q9NUW8; 27.
DR MINT; Q9NUW8; -.
DR STRING; 9606.ENSP00000337353; -.
DR BindingDB; Q9NUW8; -.
DR ChEMBL; CHEMBL1075138; -.
DR iPTMnet; Q9NUW8; -.
DR PhosphoSitePlus; Q9NUW8; -.
DR BioMuta; TDP1; -.
DR DMDM; 37999797; -.
DR EPD; Q9NUW8; -.
DR jPOST; Q9NUW8; -.
DR MassIVE; Q9NUW8; -.
DR MaxQB; Q9NUW8; -.
DR PaxDb; Q9NUW8; -.
DR PeptideAtlas; Q9NUW8; -.
DR PRIDE; Q9NUW8; -.
DR ProteomicsDB; 69739; -.
DR ProteomicsDB; 82725; -. [Q9NUW8-1]
DR Antibodypedia; 26468; 356 antibodies from 31 providers.
DR DNASU; 55775; -.
DR Ensembl; ENST00000335725.9; ENSP00000337353.4; ENSG00000042088.14. [Q9NUW8-1]
DR Ensembl; ENST00000393454.6; ENSP00000377099.2; ENSG00000042088.14. [Q9NUW8-1]
DR GeneID; 55775; -.
DR KEGG; hsa:55775; -.
DR MANE-Select; ENST00000335725.9; ENSP00000337353.4; NM_018319.4; NP_060789.2.
DR UCSC; uc001xxy.4; human. [Q9NUW8-1]
DR CTD; 55775; -.
DR DisGeNET; 55775; -.
DR GeneCards; TDP1; -.
DR HGNC; HGNC:18884; TDP1.
DR HPA; ENSG00000042088; Low tissue specificity.
DR MalaCards; TDP1; -.
DR MIM; 607198; gene.
DR MIM; 607250; phenotype.
DR neXtProt; NX_Q9NUW8; -.
DR OpenTargets; ENSG00000042088; -.
DR Orphanet; 94124; Spinocerebellar ataxia with axonal neuropathy type 1.
DR PharmGKB; PA421; -.
DR VEuPathDB; HostDB:ENSG00000042088; -.
DR eggNOG; KOG2031; Eukaryota.
DR GeneTree; ENSGT00390000002211; -.
DR HOGENOM; CLU_010413_4_0_1; -.
DR InParanoid; Q9NUW8; -.
DR OMA; PLIKECW; -.
DR OrthoDB; 1295967at2759; -.
DR PhylomeDB; Q9NUW8; -.
DR TreeFam; TF105989; -.
DR BRENDA; 3.1.4.1; 2681.
DR PathwayCommons; Q9NUW8; -.
DR Reactome; R-HSA-5693571; Nonhomologous End-Joining (NHEJ).
DR SABIO-RK; Q9NUW8; -.
DR SignaLink; Q9NUW8; -.
DR SIGNOR; Q9NUW8; -.
DR BioGRID-ORCS; 55775; 18 hits in 1082 CRISPR screens.
DR ChiTaRS; TDP1; human.
DR EvolutionaryTrace; Q9NUW8; -.
DR GeneWiki; TDP1; -.
DR GenomeRNAi; 55775; -.
DR Pharos; Q9NUW8; Tchem.
DR PRO; PR:Q9NUW8; -.
DR Proteomes; UP000005640; Chromosome 14.
DR RNAct; Q9NUW8; protein.
DR Bgee; ENSG00000042088; Expressed in oocyte and 141 other tissues.
DR ExpressionAtlas; Q9NUW8; baseline and differential.
DR Genevisible; Q9NUW8; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0017005; F:3'-tyrosyl-DNA phosphodiesterase activity; IDA:UniProtKB.
DR GO; GO:0003690; F:double-stranded DNA binding; IDA:UniProtKB.
DR GO; GO:0004527; F:exonuclease activity; IEA:UniProtKB-KW.
DR GO; GO:0003697; F:single-stranded DNA binding; IDA:UniProtKB.
DR GO; GO:0006281; P:DNA repair; IDA:UniProtKB.
DR GO; GO:0006302; P:double-strand break repair; IDA:UniProtKB.
DR GO; GO:0000012; P:single strand break repair; IDA:UniProtKB.
DR InterPro; IPR010347; Tdp1.
DR PANTHER; PTHR12415; PTHR12415; 1.
DR Pfam; PF06087; Tyr-DNA_phospho; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cytoplasm; Disease variant; DNA damage;
KW DNA repair; Exonuclease; Hydrolase; Neurodegeneration; Nuclease; Nucleus;
KW Phosphoprotein; Reference proteome; Repeat.
FT CHAIN 1..608
FT /note="Tyrosyl-DNA phosphodiesterase 1"
FT /id="PRO_0000212486"
FT REGION 1..101
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 400..403
FT /note="Interaction with DNA"
FT /evidence="ECO:0000269|PubMed:12470949"
FT COMPBIAS 13..27
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 64..88
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 263
FT /note="Nucleophile"
FT /evidence="ECO:0000269|PubMed:12470949,
FT ECO:0000269|PubMed:15111055"
FT ACT_SITE 493
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000269|PubMed:12470949,
FT ECO:0000269|PubMed:15111055"
FT BINDING 265
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:12470949"
FT BINDING 495
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:12470949"
FT SITE 518
FT /note="Interaction with DNA"
FT /evidence="ECO:0000269|PubMed:12470949"
FT MOD_RES 61
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 147
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:19690332"
FT MOD_RES 148
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19690332"
FT VAR_SEQ 1..25
FT /note="MSQEGDYGRWTISSSDESEEEKPKP -> MVISERLRLTSMPRPSLTRTSLS
FT AR (in isoform 2)"
FT /evidence="ECO:0000303|Ref.1"
FT /id="VSP_055765"
FT VAR_SEQ 26..264
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.1"
FT /id="VSP_055766"
FT VARIANT 95
FT /note="E -> D (in dbSNP:rs35114462)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_025817"
FT VARIANT 101
FT /note="P -> L (in dbSNP:rs35455108)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_025818"
FT VARIANT 134
FT /note="A -> T (in dbSNP:rs28365054)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_025819"
FT VARIANT 187
FT /note="D -> G (in dbSNP:rs35271143)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_025820"
FT VARIANT 304
FT /note="R -> Q (in dbSNP:rs34452707)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_025821"
FT VARIANT 493
FT /note="H -> R (in SCAN1; reduces enzyme activity and leads
FT to the accumulation of covalent complexes between TDP1 and
FT DNA; dbSNP:rs119467003)"
FT /evidence="ECO:0000269|PubMed:12244316,
FT ECO:0000269|PubMed:15647511, ECO:0000269|PubMed:15920477,
FT ECO:0000269|PubMed:16141202, ECO:0000269|PubMed:17948061"
FT /id="VAR_017144"
FT VARIANT 566
FT /note="P -> L (in autosomal recessive or sporadic
FT spinocerebellar ataxia affected Japanese individuals;
FT dbSNP:rs767298655)"
FT /evidence="ECO:0000269|PubMed:12244316"
FT /id="VAR_017145"
FT VARIANT 569
FT /note="T -> A (in dbSNP:rs35973343)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_025822"
FT MUTAGEN 263
FT /note="H->A: Loss of activity."
FT /evidence="ECO:0000269|PubMed:11572945,
FT ECO:0000269|PubMed:15111055"
FT MUTAGEN 265
FT /note="K->A: Abolishes hydrolysis of the covalent
FT intermediate between the active site nucleophile and DNA."
FT /evidence="ECO:0000269|PubMed:11572945,
FT ECO:0000269|PubMed:15111055"
FT MUTAGEN 265
FT /note="K->S: Reduces the activity to nearly undetectable
FT levels."
FT /evidence="ECO:0000269|PubMed:11572945,
FT ECO:0000269|PubMed:15111055"
FT MUTAGEN 283
FT /note="N->A: No effect."
FT /evidence="ECO:0000269|PubMed:15111055"
FT MUTAGEN 294
FT /note="Q->A: Slightly reduced hydrolysis of the covalent
FT intermediate between the active site nucleophile and DNA."
FT /evidence="ECO:0000269|PubMed:15111055"
FT MUTAGEN 493
FT /note="H->A: 3000-fold reduction in activity; abolishes
FT hydrolysis of the covalent intermediate between the active
FT site nucleophile and DNA."
FT /evidence="ECO:0000269|PubMed:11572945,
FT ECO:0000269|PubMed:15111055"
FT MUTAGEN 493
FT /note="H->N: 15000-fold reduction in activity."
FT /evidence="ECO:0000269|PubMed:11572945,
FT ECO:0000269|PubMed:15111055"
FT MUTAGEN 495
FT /note="K->A: Abolishes hydrolysis of the covalent
FT intermediate between the active site nucleophile and DNA."
FT /evidence="ECO:0000269|PubMed:11572945,
FT ECO:0000269|PubMed:15111055"
FT MUTAGEN 495
FT /note="K->S: 125-fold reduction in activity."
FT /evidence="ECO:0000269|PubMed:11572945,
FT ECO:0000269|PubMed:15111055"
FT MUTAGEN 516
FT /note="N->A: Reduced hydrolysis of the covalent
FT intermediate between the active site nucleophile and DNA."
FT /evidence="ECO:0000269|PubMed:15111055"
FT MUTAGEN 538
FT /note="E->A: Abolishes hydrolysis of the covalent
FT intermediate between the active site nucleophile and DNA."
FT /evidence="ECO:0000269|PubMed:15111055"
FT CONFLICT 389
FT /note="A -> P (in Ref. 2; BAA91997)"
FT /evidence="ECO:0000305"
FT CONFLICT 511
FT /note="L -> R (in Ref. 6; AAF65624)"
FT /evidence="ECO:0000305"
FT TURN 149..151
FT /evidence="ECO:0007829|PDB:1JY1"
FT HELIX 154..156
FT /evidence="ECO:0007829|PDB:1JY1"
FT STRAND 166..169
FT /evidence="ECO:0007829|PDB:6N0D"
FT HELIX 176..178
FT /evidence="ECO:0007829|PDB:6N0D"
FT TURN 179..181
FT /evidence="ECO:0007829|PDB:6N0D"
FT HELIX 185..188
FT /evidence="ECO:0007829|PDB:6N0D"
FT HELIX 191..193
FT /evidence="ECO:0007829|PDB:6N0D"
FT STRAND 196..202
FT /evidence="ECO:0007829|PDB:6N0D"
FT STRAND 204..206
FT /evidence="ECO:0007829|PDB:1RGU"
FT HELIX 208..214
FT /evidence="ECO:0007829|PDB:6N0D"
FT HELIX 217..219
FT /evidence="ECO:0007829|PDB:6N0D"
FT STRAND 224..228
FT /evidence="ECO:0007829|PDB:6N0D"
FT HELIX 232..242
FT /evidence="ECO:0007829|PDB:6N0D"
FT STRAND 248..252
FT /evidence="ECO:0007829|PDB:6N0D"
FT STRAND 266..273
FT /evidence="ECO:0007829|PDB:6N0D"
FT STRAND 275..280
FT /evidence="ECO:0007829|PDB:6N0D"
FT HELIX 286..289
FT /evidence="ECO:0007829|PDB:6N0D"
FT STRAND 291..293
FT /evidence="ECO:0007829|PDB:6N0D"
FT STRAND 295..298
FT /evidence="ECO:0007829|PDB:6N0D"
FT HELIX 319..328
FT /evidence="ECO:0007829|PDB:6N0D"
FT HELIX 333..343
FT /evidence="ECO:0007829|PDB:6N0D"
FT STRAND 352..357
FT /evidence="ECO:0007829|PDB:6N0D"
FT STRAND 359..363
FT /evidence="ECO:0007829|PDB:6N0D"
FT HELIX 364..369
FT /evidence="ECO:0007829|PDB:6N0D"
FT HELIX 371..382
FT /evidence="ECO:0007829|PDB:6N0D"
FT HELIX 389..391
FT /evidence="ECO:0007829|PDB:6N0D"
FT STRAND 394..397
FT /evidence="ECO:0007829|PDB:6N0D"
FT TURN 408..415
FT /evidence="ECO:0007829|PDB:6N0D"
FT HELIX 416..421
FT /evidence="ECO:0007829|PDB:6N0D"
FT STRAND 424..426
FT /evidence="ECO:0007829|PDB:5NWA"
FT STRAND 437..440
FT /evidence="ECO:0007829|PDB:6N0D"
FT HELIX 444..448
FT /evidence="ECO:0007829|PDB:6N0D"
FT STRAND 450..452
FT /evidence="ECO:0007829|PDB:6N0D"
FT HELIX 454..459
FT /evidence="ECO:0007829|PDB:6N0D"
FT HELIX 464..467
FT /evidence="ECO:0007829|PDB:6N0D"
FT HELIX 471..476
FT /evidence="ECO:0007829|PDB:6N0D"
FT STRAND 477..479
FT /evidence="ECO:0007829|PDB:6MZ0"
FT HELIX 483..485
FT /evidence="ECO:0007829|PDB:6N0D"
FT STRAND 490..492
FT /evidence="ECO:0007829|PDB:6W4R"
FT STRAND 495..500
FT /evidence="ECO:0007829|PDB:6N0D"
FT STRAND 504..514
FT /evidence="ECO:0007829|PDB:6N0D"
FT HELIX 519..522
FT /evidence="ECO:0007829|PDB:6N0D"
FT STRAND 524..526
FT /evidence="ECO:0007829|PDB:6N0D"
FT TURN 527..530
FT /evidence="ECO:0007829|PDB:6N0D"
FT STRAND 531..534
FT /evidence="ECO:0007829|PDB:6N0D"
FT STRAND 536..543
FT /evidence="ECO:0007829|PDB:6N0D"
FT HELIX 545..548
FT /evidence="ECO:0007829|PDB:6N0D"
FT STRAND 553..555
FT /evidence="ECO:0007829|PDB:6N0D"
FT STRAND 568..570
FT /evidence="ECO:0007829|PDB:6DJD"
SQ SEQUENCE 608 AA; 68420 MW; F30202BD8329E5CE CRC64;
MSQEGDYGRW TISSSDESEE EKPKPDKPST SSLLCARQGA ANEPRYTCSE AQKAAHKRKI
SPVKFSNTDS VLPPKRQKSG SQEDLGWCLS SSDDELQPEM PQKQAEKVVI KKEKDISAPN
DGTAQRTENH GAPACHRLKE EEDEYETSGE GQDIWDMLDK GNPFQFYLTR VSGVKPKYNS
GALHIKDILS PLFGTLVSSA QFNYCFDVDW LVKQYPPEFR KKPILLVHGD KREAKAHLHA
QAKPYENISL CQAKLDIAFG THHTKMMLLL YEEGLRVVIH TSNLIHADWH QKTQGIWLSP
LYPRIADGTH KSGESPTHFK ADLISYLMAY NAPSLKEWID VIHKHDLSET NVYLIGSTPG
RFQGSQKDNW GHFRLKKLLK DHASSMPNAE SWPVVGQFSS VGSLGADESK WLCSEFKESM
LTLGKESKTP GKSSVPLYLI YPSVENVRTS LEGYPAGGSL PYSIQTAEKQ NWLHSYFHKW
SAETSGRSNA MPHIKTYMRP SPDFSKIAWF LVTSANLSKA AWGALEKNGT QLMIRSYELG
VLFLPSAFGL DSFKVKQKFF AGSQEPMATF PVPYDLPPEL YGSKDRPWIW NIPYVKAPDT
HGNMWVPS
