ID TYDP2_HUMAN Reviewed; 362 AA. AC O95551; B4DKL8; B4DQ95; Q2TBE2; Q5JYM0; Q7Z6U5; Q9NUK5; Q9NYY9; DT 07-JUN-2005, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1999, sequence version 1. DT 27-MAR-2024, entry version 180. DE RecName: Full=Tyrosyl-DNA phosphodiesterase 2; DE Short=Tyr-DNA phosphodiesterase 2 {ECO:0000303|PubMed:19794497}; DE Short=hTDP2; DE EC=3.1.4.- {ECO:0000269|PubMed:19794497, ECO:0000269|PubMed:22405347, ECO:0000269|PubMed:22822062, ECO:0000269|PubMed:27060144, ECO:0000269|PubMed:27099339}; DE AltName: Full=5'-tyrosyl-DNA phosphodiesterase {ECO:0000303|PubMed:19794497}; DE Short=5'-Tyr-DNA phosphodiesterase; DE AltName: Full=ETS1-associated protein 2; DE AltName: Full=ETS1-associated protein II; DE Short=EAPII {ECO:0000303|PubMed:12743594}; DE AltName: Full=TRAF and TNF receptor-associated protein; DE AltName: Full=Tyrosyl-RNA phosphodiesterase; DE AltName: Full=VPg unlinkase; GN Name=TDP2 {ECO:0000303|PubMed:27060144}; GN Synonyms=EAP2 {ECO:0000303|PubMed:12743594}, TTRAP GN {ECO:0000303|PubMed:10764746, ECO:0000303|PubMed:19794497}; GN ORFNames=AD-022; 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 [MRNA] (ISOFORM 1), INTERACTION WITH TNFRSF5; TNFRSF8; RP TNFRSF1B; TRAF2; TRAF3; TRAF5 AND TRAF6, AND TISSUE SPECIFICITY. RC TISSUE=Umbilical vein; RX PubMed=10764746; DOI=10.1074/jbc.m000531200; RA Pype S., Declercq W., Ibrahimi A., Michiels C., Van Rietschoten J.G.I., RA Dewulf N., de Boer M., Vandenabeele P., Huylebroeck D., Remacle J.E.; RT "TTRAP, a novel protein that associates with CD40, tumor necrosis factor RT (TNF) receptor-75 and TNF receptor-associated factors (TRAFs), and that RT inhibits nuclear factor-kappa B activation."; RL J. Biol. Chem. 275:18586-18593(2000). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH ETS1; ETS2 AND RP FLI1, AND SUBCELLULAR LOCATION. RX PubMed=12743594; DOI=10.1038/sj.onc.1206374; RA Pei H., Yordy J.S., Leng Q., Zhao Q., Watson D.K., Li R.; RT "EAPII interacts with ETS1 and modulates its transcriptional function."; RL Oncogene 22:2699-2709(2003). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Adrenal gland; RX PubMed=10931946; DOI=10.1073/pnas.160270997; RA Hu R.-M., Han Z.-G., Song H.-D., Peng Y.-D., Huang Q.-H., Ren S.-X., RA Gu Y.-J., Huang C.-H., Li Y.-B., Jiang C.-L., Fu G., Zhang Q.-H., Gu B.-W., RA Dai M., Mao Y.-F., Gao G.-F., Rong R., Ye M., Zhou J., Xu S.-H., Gu J., RA Shi J.-X., Jin W.-R., Zhang C.-K., Wu T.-M., Huang G.-Y., Chen Z., RA Chen M.-D., Chen J.-L.; RT "Gene expression profiling in the human hypothalamus-pituitary-adrenal axis RT and full-length cDNA cloning."; RL Proc. Natl. Acad. Sci. U.S.A. 97:9543-9548(2000). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND NUCLEOTIDE RP SEQUENCE [LARGE SCALE MRNA] OF 23-362 (ISOFORM 3). RC TISSUE=Colon, and 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 [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLU-249 AND GLN-268. RG SeattleSNPs variation discovery resource; RL Submitted (APR-2004) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=14574404; DOI=10.1038/nature02055; RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., RA Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Duodenum, and Skin; 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 [8] RP INTERACTION WITH HANTAAN HANTAVIRUS NUCLEOPROTEIN (MICROBIAL INFECTION), RP AND INTERACTION WITH SEOUL HANTAVIRUS NUCLEOPROTEIN (MICROBIAL INFECTION). RX PubMed=14609633; DOI=10.1016/j.virusres.2003.09.001; RA Lee B.H., Yoshimatsu K., Maeda A., Ochiai K., Morimatsu M., Araki K., RA Ogino M., Morikawa S., Arikawa J.; RT "Association of the nucleocapsid protein of the Seoul and Hantaan RT hantaviruses with small ubiquitin-like modifier-1-related molecules."; RL Virus Res. 98:83-91(2003). RN [9] RP INTERACTION WITH ACVR1B AND SMAD3, PHOSPHORYLATION AT THR-88 AND THR-92, RP AND MUTAGENESIS OF THR-88 AND THR-92. 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 [10] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [11] RP FUNCTION AS TYROSYL-DNA PHOSPHODIESTERASE, CATALYTIC ACTIVITY, SUBCELLULAR RP LOCATION, COFACTOR, AND MUTAGENESIS OF GLU-152 AND ASP-262. RX PubMed=19794497; DOI=10.1038/nature08444; RA Ledesma F.C., El Khamisy S.F., Zuma M.C., Osborn K., Caldecott K.W.; RT "A human 5'-tyrosyl DNA phosphodiesterase that repairs topoisomerase- RT mediated DNA damage."; RL Nature 461:674-678(2009). RN [12] 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 [13] RP FUNCTION. RX PubMed=21030584; DOI=10.1074/jbc.m110.181016; RA Zeng Z., Cortes-Ledesma F., El Khamisy S.F., Caldecott K.W.; RT "TDP2/TTRAP is the major 5'-tyrosyl DNA phosphodiesterase activity in RT vertebrate cells and is critical for cellular resistance to topoisomerase RT II-induced DNA damage."; RL J. Biol. Chem. 286:403-409(2011). RN [14] RP FUNCTION, AND UBIQUITINATION. RX PubMed=21980489; DOI=10.1371/journal.pone.0025548; RA Varady G., Sarkadi B., Fatyol K.; RT "TTRAP is a novel component of the non-canonical TRAF6-TAK1 TGF-beta RT signaling pathway."; RL PLoS ONE 6:E25548-E25548(2011). RN [15] RP FUNCTION, CATALYTIC ACTIVITY, AND COFACTOR. RX PubMed=22405347; DOI=10.1186/1756-0500-5-134; RA Adhikari S., Karmahapatra S.K., Karve T.M., Bandyopadhyay S., Woodrick J., RA Manthena P.V., Glasgow E., Byers S., Saha T., Uren A.; RT "Characterization of magnesium requirement of human 5'-tyrosyl DNA RT phosphodiesterase mediated reaction."; RL BMC Res. Notes 5:134-134(2012). RN [16] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=21921940; DOI=10.1038/cdd.2011.118; RA Vilotti S., Biagioli M., Foti R., Dal Ferro M., Lavina Z.S., Collavin L., RA Del Sal G., Zucchelli S., Gustincich S.; RT "The PML nuclear bodies-associated protein TTRAP regulates ribosome RT biogenesis in nucleolar cavities upon proteasome inhibition."; RL Cell Death Differ. 19:488-500(2012). RN [17] RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES, AND RP MUTAGENESIS OF ASN-120; GLU-152; ASP-262 AND HIS-351. 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 [18] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22223895; DOI=10.1074/mcp.m111.015131; RA Bienvenut W.V., Sumpton D., Martinez A., Lilla S., Espagne C., Meinnel T., RA Giglione C.; RT "Comparative large-scale characterisation of plant vs. mammal proteins RT reveals similar and idiosyncratic N-alpha acetylation features."; RL Mol. Cell. Proteomics 11:M111.015131-M111.015131(2012). RN [19] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22814378; DOI=10.1073/pnas.1210303109; RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.; RT "N-terminal acetylome analyses and functional insights of the N-terminal RT acetyltransferase NatB."; RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012). RN [20] RP FUNCTION AS TYROSYL-RNA PHOSPHODIESTERASE (MICROBIAL INFECTION), AND RP SUBCELLULAR LOCATION (MICROBIAL INFECTION). RX PubMed=22908287; DOI=10.1073/pnas.1208096109; RA Virgen-Slane R., Rozovics J.M., Fitzgerald K.D., Ngo T., Chou W., RA van der Heden van Noort G.J., Filippov D.V., Gershon P.D., Semler B.L.; RT "An RNA virus hijacks an incognito function of a DNA repair enzyme."; RL Proc. Natl. Acad. Sci. U.S.A. 109:14634-14639(2012). RN [21] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-95, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=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 [22] RP FUNCTION, TISSUE SPECIFICITY, INVOLVEMENT IN SCAR23, AND VARIANT VAL-307. RX PubMed=24658003; DOI=10.1038/ng.2929; RA Gomez-Herreros F., Schuurs-Hoeijmakers J.H., McCormack M., Greally M.T., RA Rulten S., Romero-Granados R., Counihan T.J., Chaila E., Conroy J., RA Ennis S., Delanty N., Cortes-Ledesma F., de Brouwer A.P., Cavalleri G.L., RA El-Khamisy S.F., de Vries B.B., Caldecott K.W.; RT "TDP2 protects transcription from abortive topoisomerase activity and is RT required for normal neural function."; RL Nat. Genet. 46:516-521(2014). RN [23] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-23 AND LYS-82, AND IDENTIFICATION RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=28112733; DOI=10.1038/nsmb.3366; RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C., RA Nielsen M.L.; RT "Site-specific mapping of the human SUMO proteome reveals co-modification RT with phosphorylation."; RL Nat. Struct. Mol. Biol. 24:325-336(2017). RN [24] {ECO:0007744|PDB:5J3P, ECO:0007744|PDB:5J3S} RP X-RAY CRYSTALLOGRAPHY (3.10 ANGSTROMS) OF 113-362, FUNCTION, CATALYTIC RP ACTIVITY, AND COFACTOR. RX PubMed=27099339; DOI=10.1042/bcj20160180; RA Hornyak P., Askwith T., Walker S., Komulainen E., Paradowski M., RA Pennicott L.E., Bartlett E.J., Brissett N.C., Raoof A., Watson M., RA Jordan A.M., Ogilvie D.J., Ward S.E., Atack J.R., Pearl L.H., RA Caldecott K.W., Oliver A.W.; RT "Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA RT phosphodiesterase 2."; RL Biochem. J. 473:1869-1879(2016). RN [25] {ECO:0007744|PDB:5INO} RP X-RAY CRYSTALLOGRAPHY (3.21 ANGSTROMS) OF 108-362 IN COMPLEX WITH DNA, RP FUNCTION, CATALYTIC ACTIVITY, COFACTOR, ACTIVE SITE, CHARACTERIZATION OF RP VARIANT VAL-307, AND MUTAGENESIS OF TYR-178; ARG-206; ASP-262; LEU-305; RP ASP-316; ASP-350 AND HIS-351. RX PubMed=27060144; DOI=10.1093/nar/gkw228; RA Schellenberg M.J., Perera L., Strom C.N., Waters C.A., Monian B., RA Appel C.D., Vilas C.K., Williams J.G., Ramsden D.A., Williams R.S.; RT "Reversal of DNA damage induced Topoisomerase 2 DNA-protein crosslinks by RT Tdp2."; RL Nucleic Acids Res. 44:3829-3844(2016). 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. The 5'-tyrosyl DNA phosphodiesterase activity can CC enable the repair of TOP2-induced DNA double-strand breaks/DSBs without CC the need for nuclease activity, creating a 'clean' DSB with 5'- CC phosphate termini that are ready for ligation (PubMed:27099339, CC PubMed:27060144). Thereby, protects the transcription of many genes CC involved in neurological development and maintenance from the abortive CC activity of TOP2. Hydrolyzes 5'-phosphoglycolates on protruding 5' ends CC on DSBs due to DNA damage by radiation and free radicals. Has CC preference for single-stranded DNA or duplex DNA with a 4 base pair CC overhang as substrate. Acts as a regulator of ribosome biogenesis CC following stress. Has also 3'-tyrosyl DNA phosphodiesterase activity, CC but less efficiently and much slower than TDP1. Constitutes the major CC if not only 5'-tyrosyl-DNA phosphodiesterase in cells. Also acts as an CC adapter by participating in the specific activation of MAP3K7/TAK1 in CC response to TGF-beta: associates with components of the TGF-beta CC receptor-TRAF6-TAK1 signaling module and promotes their ubiquitination CC dependent complex formation. Involved in non-canonical TGF-beta induced CC signaling routes. May also act as a negative regulator of ETS1 and may CC inhibit NF-kappa-B activation. {ECO:0000269|PubMed:19794497, CC ECO:0000269|PubMed:21030584, ECO:0000269|PubMed:21921940, CC ECO:0000269|PubMed:21980489, ECO:0000269|PubMed:22405347, CC ECO:0000269|PubMed:22822062, ECO:0000269|PubMed:24658003, CC ECO:0000269|PubMed:27060144, ECO:0000269|PubMed:27099339}. CC -!- FUNCTION: (Microbial infection) Also acts as a 5'-tyrosyl-RNA CC phosphodiesterase following picornavirus infection: its activity is CC hijacked by picornavirus and acts by specifically cleaving the protein- CC RNA covalent linkage generated during the viral genomic RNA replication CC steps of a picornavirus infection, without impairing the integrity of CC viral RNA. {ECO:0000269|PubMed:22908287}. CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:19794497, ECO:0000269|PubMed:22405347, CC ECO:0000269|PubMed:22822062, ECO:0000269|PubMed:27060144, CC ECO:0000269|PubMed:27099339}; CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035; CC Evidence={ECO:0000269|PubMed:19794497, ECO:0000269|PubMed:22405347, CC ECO:0000269|PubMed:22822062}; CC Note=Binds 1 magnesium or manganese ion per subunit. CC {ECO:0000269|PubMed:19794497, ECO:0000269|PubMed:22405347, CC ECO:0000269|PubMed:22822062, ECO:0000269|PubMed:27060144, CC ECO:0000269|PubMed:27099339}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=8 uM for single-stranded 5'-tyrosyl DNA CC {ECO:0000269|PubMed:22822062}; CC Note=kcat is 3 sec(-1) with single-stranded 5'-tyrosyl DNA as CC substrate.; CC -!- SUBUNIT: Interacts with TRAF2, TRAF3, TRAF5, TRAF6, TNFRSF8/CD30, CC TNFRSF5/CD40, TNFRSF1B/TNF-R75, ETS1, ETS2, FLI1, SMAD3 and CC ACVR1B/ALK4. {ECO:0000269|PubMed:10764746, ECO:0000269|PubMed:12743594, CC ECO:0000269|PubMed:18039968}. CC -!- SUBUNIT: (Microbial infection) Interacts with Hantaan hantavirus CC nucleoprotein. {ECO:0000269|PubMed:14609633}. CC -!- SUBUNIT: (Microbial infection) Interacts with Seoul hantavirus CC nucleoprotein. {ECO:0000269|PubMed:14609633}. CC -!- INTERACTION: CC O95551; P54252: ATXN3; NbExp=3; IntAct=EBI-2819865, EBI-946046; CC O95551; P51451: BLK; NbExp=3; IntAct=EBI-2819865, EBI-2105445; CC O95551; P50570-2: DNM2; NbExp=3; IntAct=EBI-2819865, EBI-10968534; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:12743594}. Nucleus, CC PML body {ECO:0000269|PubMed:19794497, ECO:0000269|PubMed:21921940}. CC Nucleus, nucleolus {ECO:0000269|PubMed:21921940}. Cytoplasm. CC Note=Localizes to nucleolar cavities following stress; localization to CC nucleolus is dependent on PML protein. {ECO:0000269|PubMed:21921940}. CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:22908287}. CC Note=(Microbial infection) In case of infection by picornavirus, CC relocalizes to cytoplasmic sites distinct from those containing viral CC proteins associated with RNA replication or encapsidation. CC {ECO:0000269|PubMed:22908287}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=O95551-1; Sequence=Displayed; CC Name=2; CC IsoId=O95551-2; Sequence=VSP_038523; CC Name=3; CC IsoId=O95551-3; Sequence=VSP_038524; CC -!- TISSUE SPECIFICITY: Widely expressed (PubMed:10764746). Highly CC expressed in various brain regions, including the frontal and occipital CC lobes, the hippocampus, the striatum and the cerebellum CC (PubMed:24658003). {ECO:0000269|PubMed:10764746, CC ECO:0000269|PubMed:24658003}. CC -!- PTM: Ubiquitinated by TRAF6. {ECO:0000269|PubMed:21980489}. CC -!- DISEASE: Spinocerebellar ataxia, autosomal recessive, 23 (SCAR23) CC [MIM:616949]: A form of spinocerebellar ataxia, a clinically and CC genetically heterogeneous group of cerebellar disorders due to CC degeneration of the cerebellum with variable involvement of the CC brainstem and spinal cord. SCAR23 patients manifest epilepsy, CC intellectual disability, and gait ataxia. CC {ECO:0000269|PubMed:24658003}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the CCR4/nocturin family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAG59230.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=SeattleSNPs; CC URL="http://pga.gs.washington.edu/data/ttrap/"; 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; AJ269473; CAB92966.1; -; mRNA. DR EMBL; AF201687; AAG35600.1; -; mRNA. DR EMBL; AF223469; AAF64144.1; -; mRNA. DR EMBL; AK002168; BAA92119.1; -; mRNA. DR EMBL; AK296623; BAG59230.1; ALT_INIT; mRNA. DR EMBL; AK298699; BAG60857.1; -; mRNA. DR EMBL; AY613922; AAT09764.1; -; Genomic_DNA. DR EMBL; AL031775; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC017553; AAH17553.1; -; mRNA. DR EMBL; BC110375; AAI10376.1; -; mRNA. DR CCDS; CCDS4557.1; -. [O95551-1] DR RefSeq; NP_057698.2; NM_016614.2. [O95551-1] DR PDB; 5INO; X-ray; 3.21 A; A/B=108-362. DR PDB; 5J3P; X-ray; 3.10 A; A/B=113-362. DR PDB; 5J3S; X-ray; 3.40 A; A=113-362. DR PDB; 6Q00; X-ray; 0.85 A; B=25-66. DR PDB; 6Q01; X-ray; 0.85 A; C/D=25-66. DR PDBsum; 5INO; -. DR PDBsum; 5J3P; -. DR PDBsum; 5J3S; -. DR PDBsum; 6Q00; -. DR PDBsum; 6Q01; -. DR AlphaFoldDB; O95551; -. DR SMR; O95551; -. DR BioGRID; 119615; 72. DR IntAct; O95551; 49. DR MINT; O95551; -. DR STRING; 9606.ENSP00000367440; -. DR BindingDB; O95551; -. DR ChEMBL; CHEMBL2169736; -. DR GlyGen; O95551; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; O95551; -. DR PhosphoSitePlus; O95551; -. DR BioMuta; TDP2; -. DR EPD; O95551; -. DR jPOST; O95551; -. DR MassIVE; O95551; -. DR MaxQB; O95551; -. DR PaxDb; 9606-ENSP00000367440; -. DR PeptideAtlas; O95551; -. DR ProteomicsDB; 50937; -. [O95551-1] DR ProteomicsDB; 50938; -. [O95551-2] DR ProteomicsDB; 50939; -. [O95551-3] DR Pumba; O95551; -. DR Antibodypedia; 10651; 363 antibodies from 33 providers. DR CPTC; O95551; 3 antibodies. DR DNASU; 51567; -. DR Ensembl; ENST00000378198.9; ENSP00000367440.4; ENSG00000111802.14. [O95551-1] DR GeneID; 51567; -. DR KEGG; hsa:51567; -. DR MANE-Select; ENST00000378198.9; ENSP00000367440.4; NM_016614.3; NP_057698.2. DR UCSC; uc003nej.4; human. [O95551-1] DR AGR; HGNC:17768; -. DR DisGeNET; 51567; -. DR GeneCards; TDP2; -. DR HGNC; HGNC:17768; TDP2. DR HPA; ENSG00000111802; Tissue enhanced (intestine). DR MalaCards; TDP2; -. DR MIM; 605764; gene. DR MIM; 616949; phenotype. DR neXtProt; NX_O95551; -. DR OpenTargets; ENSG00000111802; -. DR Orphanet; 404493; Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to TUD deficiency. DR PharmGKB; PA165618310; -. DR VEuPathDB; HostDB:ENSG00000111802; -. DR eggNOG; KOG2756; Eukaryota. DR GeneTree; ENSGT00390000014242; -. DR HOGENOM; CLU_047318_0_0_1; -. DR InParanoid; O95551; -. DR OMA; AENDWDM; -. DR OrthoDB; 276861at2759; -. DR PhylomeDB; O95551; -. DR TreeFam; TF314813; -. DR PathwayCommons; O95551; -. DR Reactome; R-HSA-5693571; Nonhomologous End-Joining (NHEJ). DR SignaLink; O95551; -. DR SIGNOR; O95551; -. DR BioGRID-ORCS; 51567; 122 hits in 1161 CRISPR screens. DR ChiTaRS; TDP2; human. DR GeneWiki; TTRAP; -. DR GenomeRNAi; 51567; -. DR Pharos; O95551; Tchem. DR PRO; PR:O95551; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; O95551; Protein. DR Bgee; ENSG00000111802; Expressed in jejunal mucosa and 213 other cell types or tissues. DR ExpressionAtlas; O95551; baseline and differential. DR GO; GO:0016235; C:aggresome; IDA:HPA. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0016604; C:nuclear body; IDA:HPA. DR GO; GO:0005730; C:nucleolus; IEA:UniProtKB-SubCell. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0016605; C:PML body; IDA:UniProtKB. DR GO; GO:0070260; F:5'-tyrosyl-DNA phosphodiesterase activity; IDA:UniProtKB. DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB. DR GO; GO:0030145; F:manganese ion binding; IDA:UniProtKB. DR GO; GO:0004518; F:nuclease activity; IEA:UniProtKB-KW. DR GO; GO:0003697; F:single-stranded DNA binding; IDA:UniProtKB. DR GO; GO:0003714; F:transcription corepressor activity; TAS:ProtInc. DR GO; GO:0036317; F:tyrosyl-RNA phosphodiesterase activity; IDA:UniProtKB. DR GO; GO:0007166; P:cell surface receptor signaling pathway; TAS:ProtInc. DR GO; GO:0006302; P:double-strand break repair; IDA:UniProtKB. DR GO; GO:0048666; P:neuron development; IMP:UniProtKB. DR CDD; cd09080; TDP2; 1. DR CDD; cd14344; UBA_TYDP2; 1. DR Gene3D; 1.10.8.10; DNA helicase RuvA subunit, C-terminal domain; 1. DR Gene3D; 3.60.10.10; Endonuclease/exonuclease/phosphatase; 1. DR InterPro; IPR036691; Endo/exonu/phosph_ase_sf. DR InterPro; IPR005135; Endo/exonuclease/phosphatase. DR InterPro; IPR009060; UBA-like_sf. DR PANTHER; PTHR15822; TRAF AND TNF RECEPTOR-ASSOCIATED PROTEIN; 1. DR PANTHER; PTHR15822:SF4; TYROSYL-DNA PHOSPHODIESTERASE 2; 1. DR Pfam; PF03372; Exo_endo_phos; 1. DR Pfam; PF14555; UBA_4; 1. DR SUPFAM; SSF56219; DNase I-like; 1. DR SUPFAM; SSF46934; UBA-like; 1. DR Genevisible; O95551; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Alternative splicing; Cytoplasm; DNA damage; KW DNA repair; Host-virus interaction; Hydrolase; Intellectual disability; KW Isopeptide bond; Magnesium; Metal-binding; Neurodegeneration; Nuclease; KW Nucleus; Phosphoprotein; Reference proteome; Spinocerebellar ataxia; KW Ubl conjugation. FT CHAIN 1..362 FT /note="Tyrosyl-DNA phosphodiesterase 2" FT /id="PRO_0000065678" FT REGION 1..20 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 87..109 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 120..124 FT /note="Interaction with 5' end of substrate DNA" FT /evidence="ECO:0000250|UniProtKB:Q9JJX7" FT REGION 226..231 FT /note="Interaction with 5' end of substrate DNA" FT /evidence="ECO:0000250|UniProtKB:Q9JJX7" FT REGION 264..266 FT /note="Interaction with 5' end of substrate DNA" FT /evidence="ECO:0000250|UniProtKB:Q9JJX7" FT ACT_SITE 262 FT /note="Proton donor/acceptor" FT /evidence="ECO:0000305|PubMed:27060144" FT BINDING 122 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000269|PubMed:27099339, FT ECO:0007744|PDB:5J3P" FT BINDING 152 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /evidence="ECO:0000269|PubMed:27099339, FT ECO:0007744|PDB:5J3P" FT SITE 178 FT /note="Interaction with 5' end of substrate DNA" FT /evidence="ECO:0000250|UniProtKB:Q9JJX7" FT SITE 297 FT /note="Interaction with 5' end of substrate DNA" FT /evidence="ECO:0000250|UniProtKB:Q9JJX7" FT SITE 315 FT /note="Interaction with 5' end of substrate DNA" FT /evidence="ECO:0000250|UniProtKB:Q9JJX7" FT SITE 351 FT /note="Interaction with 5' end of substrate DNA" FT /evidence="ECO:0000250|UniProtKB:Q9JJX7" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0007744|PubMed:19413330, FT ECO:0007744|PubMed:22223895, ECO:0007744|PubMed:22814378" FT MOD_RES 88 FT /note="Phosphothreonine; by ACVR1B" FT /evidence="ECO:0000269|PubMed:18039968" FT MOD_RES 92 FT /note="Phosphothreonine; by ACVR1B" FT /evidence="ECO:0000269|PubMed:18039968" FT MOD_RES 95 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT CROSSLNK 23 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT CROSSLNK 82 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT VAR_SEQ 1 FT /note="M -> MRERHDTGACAEPRVGLLFRLKGRCRGGRKM (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_038523" FT VAR_SEQ 60..137 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_038524" FT VARIANT 166 FT /note="S -> G (in dbSNP:rs35977478)" FT /id="VAR_051464" FT VARIANT 249 FT /note="Q -> E (in dbSNP:rs2294689)" FT /evidence="ECO:0000269|Ref.5" FT /id="VAR_022634" FT VARIANT 268 FT /note="R -> Q (in dbSNP:rs17249952)" FT /evidence="ECO:0000269|Ref.5" FT /id="VAR_022635" FT VARIANT 307 FT /note="I -> V (slightly decreased phosphodiesterase FT activity; dbSNP:rs77273535)" FT /evidence="ECO:0000269|PubMed:24658003" FT /id="VAR_076867" FT MUTAGEN 88 FT /note="T->A: Abolishes function, but retains ability to FT interact with SMAD3; when associated with A-92." FT /evidence="ECO:0000269|PubMed:18039968" FT MUTAGEN 92 FT /note="T->A: Abolishes function, but retains ability to FT interact with SMAD3; when associated with A-88." FT /evidence="ECO:0000269|PubMed:18039968" FT MUTAGEN 120 FT /note="N->A: Strongly reduced phosphodiesterase activity." FT /evidence="ECO:0000269|PubMed:22822062" FT MUTAGEN 152 FT /note="E->A: Loss of phosphodiesterase activity." FT /evidence="ECO:0000269|PubMed:19794497, FT ECO:0000269|PubMed:22822062" FT MUTAGEN 178 FT /note="Y->F,W: Strongly decreased phosphodiesterase FT activity." FT /evidence="ECO:0000269|PubMed:27060144" FT MUTAGEN 206 FT /note="R->A,K: Loss of phosphodiesterase activity." FT /evidence="ECO:0000269|PubMed:27060144" FT MUTAGEN 262 FT /note="D->A: Loss of phosphodiesterase activity." FT /evidence="ECO:0000269|PubMed:19794497, FT ECO:0000269|PubMed:22822062" FT MUTAGEN 262 FT /note="D->H,L,M: Loss of phosphodiesterase activity." FT /evidence="ECO:0000269|PubMed:27060144" FT MUTAGEN 305 FT /note="L->A,F,W: Decreased phosphodiesterase activity." FT /evidence="ECO:0000269|PubMed:27060144" FT MUTAGEN 316 FT /note="D->N: Strongly decreased phosphodiesterase FT activity." FT /evidence="ECO:0000269|PubMed:27060144" FT MUTAGEN 350 FT /note="D->N: Strongly decreased phosphodiesterase FT activity." FT /evidence="ECO:0000269|PubMed:27060144" FT MUTAGEN 351 FT /note="H->A: Loss of phosphodiesterase activity." FT /evidence="ECO:0000269|PubMed:22822062" FT MUTAGEN 351 FT /note="H->Q: Loss of phosphodiesterase activity." FT /evidence="ECO:0000269|PubMed:27060144" FT CONFLICT 31 FT /note="E -> R (in Ref. 3; AAF64144)" FT /evidence="ECO:0000305" FT CONFLICT 61 FT /note="Y -> C (in Ref. 4; BAA92119)" FT /evidence="ECO:0000305" FT CONFLICT 72 FT /note="E -> G (in Ref. 4; BAG60857)" FT /evidence="ECO:0000305" FT HELIX 25..36 FT /evidence="ECO:0007829|PDB:6Q00" FT HELIX 40..49 FT /evidence="ECO:0007829|PDB:6Q00" FT TURN 50..52 FT /evidence="ECO:0007829|PDB:6Q00" FT HELIX 54..62 FT /evidence="ECO:0007829|PDB:6Q00" FT STRAND 113..120 FT /evidence="ECO:0007829|PDB:5J3P" FT HELIX 129..143 FT /evidence="ECO:0007829|PDB:5J3P" FT STRAND 146..153 FT /evidence="ECO:0007829|PDB:5J3P" FT HELIX 155..164 FT /evidence="ECO:0007829|PDB:5J3P" FT STRAND 167..173 FT /evidence="ECO:0007829|PDB:5J3P" FT STRAND 175..177 FT /evidence="ECO:0007829|PDB:5J3P" FT STRAND 179..185 FT /evidence="ECO:0007829|PDB:5J3P" FT TURN 186..188 FT /evidence="ECO:0007829|PDB:5J3P" FT STRAND 189..198 FT /evidence="ECO:0007829|PDB:5J3P" FT STRAND 203..205 FT /evidence="ECO:0007829|PDB:5J3S" FT STRAND 207..215 FT /evidence="ECO:0007829|PDB:5J3P" FT STRAND 218..224 FT /evidence="ECO:0007829|PDB:5J3P" FT HELIX 231..233 FT /evidence="ECO:0007829|PDB:5INO" FT HELIX 234..249 FT /evidence="ECO:0007829|PDB:5J3P" FT STRAND 255..262 FT /evidence="ECO:0007829|PDB:5J3P" FT HELIX 269..272 FT /evidence="ECO:0007829|PDB:5J3P" FT HELIX 283..286 FT /evidence="ECO:0007829|PDB:5J3P" FT STRAND 291..294 FT /evidence="ECO:0007829|PDB:5INO" FT STRAND 296..298 FT /evidence="ECO:0007829|PDB:5J3P" FT TURN 299..301 FT /evidence="ECO:0007829|PDB:5J3P" FT STRAND 316..321 FT /evidence="ECO:0007829|PDB:5J3P" FT STRAND 329..337 FT /evidence="ECO:0007829|PDB:5J3P" FT STRAND 353..360 FT /evidence="ECO:0007829|PDB:5J3P" SQ SEQUENCE 362 AA; 40930 MW; 37892E125DB64410 CRC64; MELGSCLEGG REAAEEEGEP EVKKRRLLCV EFASVASCDA AVAQCFLAEN DWEMERALNS YFEPPVEESA LERRPETISE PKTYVDLTNE ETTDSTTSKI SPSEDTQQEN GSMFSLITWN IDGLDLNNLS ERARGVCSYL ALYSPDVIFL QEVIPPYYSY LKKRSSNYEI ITGHEEGYFT AIMLKKSRVK LKSQEIIPFP STKMMRNLLC VHVNVSGNEL CLMTSHLEST RGHAAERMNQ LKMVLKKMQE APESATVIFA GDTNLRDREV TRCGGLPNNI VDVWEFLGKP KHCQYTWDTQ MNSNLGITAA CKLRFDRIFF RAAAEEGHII PRSLDLLGLE KLDCGRFPSD HWGLLCNLDI IL //