TYDP2_HUMAN
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 03-AUG-2022, entry version 172.
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},
GN TTRAP {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/";
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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; 65.
DR IntAct; O95551; 47.
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; O95551; -.
DR PeptideAtlas; O95551; -.
DR PRIDE; O95551; -.
DR ProteomicsDB; 50937; -. [O95551-1]
DR ProteomicsDB; 50938; -. [O95551-2]
DR ProteomicsDB; 50939; -. [O95551-3]
DR Antibodypedia; 10651; 309 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 CTD; 51567; -.
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; 1612152at2759; -.
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; 105 hits in 1084 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 211 other tissues.
DR ExpressionAtlas; O95551; baseline and differential.
DR Genevisible; O95551; HS.
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 Gene3D; 3.60.10.10; -; 1.
DR InterPro; IPR036691; Endo/exonu/phosph_ase_sf.
DR InterPro; IPR005135; Endo/exonuclease/phosphatase.
DR InterPro; IPR009060; UBA-like_sf.
DR Pfam; PF03372; Exo_endo_phos; 1.
DR SUPFAM; SSF46934; SSF46934; 1.
DR SUPFAM; SSF56219; SSF56219; 1.
PE 1: Evidence at protein level;
KW 3D-structure; 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
