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 24-JAN-2024, entry version 182. 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/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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. 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 PDB; 7UFY; X-ray; 1.58 A; A/B=148-608. DR PDB; 7UFZ; X-ray; 1.56 A; A/B=148-608. DR PDB; 8CVQ; X-ray; 1.65 A; A/B=148-608. DR PDB; 8CW2; X-ray; 1.81 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 PDBsum; 7UFY; -. DR PDBsum; 7UFZ; -. DR PDBsum; 8CVQ; -. DR PDBsum; 8CW2; -. DR AlphaFoldDB; Q9NUW8; -. DR SASBDB; Q9NUW8; -. DR SMR; Q9NUW8; -. DR BioGRID; 120890; 31. DR ComplexPortal; CPX-793; XRCC1 DNA repair complex. DR CORUM; Q9NUW8; -. DR IntAct; Q9NUW8; 27. DR MINT; Q9NUW8; -. DR STRING; 9606.ENSP00000337353; -. DR BindingDB; Q9NUW8; -. DR ChEMBL; CHEMBL1075138; -. DR GlyGen; Q9NUW8; 8 sites, 1 O-linked glycan (8 sites). 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; 9606-ENSP00000337353; -. DR PeptideAtlas; Q9NUW8; -. DR ProteomicsDB; 69739; -. DR ProteomicsDB; 82725; -. [Q9NUW8-1] DR Pumba; Q9NUW8; -. DR Antibodypedia; 26468; 381 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 AGR; HGNC:18884; -. DR CTD; 55775; -. DR DisGeNET; 55775; -. DR GeneCards; TDP1; -. DR GeneReviews; 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; 930461at2759; -. 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; 20 hits in 1161 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 143 other cell types or tissues. DR ExpressionAtlas; Q9NUW8; baseline and differential. 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 CDD; cd09193; PLDc_mTdp1_1; 1. DR CDD; cd09195; PLDc_mTdp1_2; 1. DR Gene3D; 3.30.870.10; Endonuclease Chain A; 2. DR InterPro; IPR010347; Tdp1. DR PANTHER; PTHR12415; TYROSYL-DNA PHOSPHODIESTERASE 1; 1. DR PANTHER; PTHR12415:SF0; TYROSYL-DNA PHOSPHODIESTERASE 1; 1. DR Pfam; PF06087; Tyr-DNA_phospho; 1. DR SUPFAM; SSF56024; Phospholipase D/nuclease; 2. DR Genevisible; Q9NUW8; HS. 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:7UFY" 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 //