Full text data of USP7
USP7
(HAUSP)
[Confidence: high (present in two of the MS resources)]
Ubiquitin carboxyl-terminal hydrolase 7; 3.4.19.12 (Deubiquitinating enzyme 7; Herpesvirus-associated ubiquitin-specific protease; Ubiquitin thioesterase 7; Ubiquitin-specific-processing protease 7)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Ubiquitin carboxyl-terminal hydrolase 7; 3.4.19.12 (Deubiquitinating enzyme 7; Herpesvirus-associated ubiquitin-specific protease; Ubiquitin thioesterase 7; Ubiquitin-specific-processing protease 7)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00003965
IPI00003965 Ubiquitin-specific protease 7 isoform Cleaves ubiquitin fusion protein substrates, Ubiquitin C-terminal thiolester + H2O = ubiquitin + a thiol soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a nuclear n/a expected molecular weight found in band found in band >188 kDa
IPI00003965 Ubiquitin-specific protease 7 isoform Cleaves ubiquitin fusion protein substrates, Ubiquitin C-terminal thiolester + H2O = ubiquitin + a thiol soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a nuclear n/a expected molecular weight found in band found in band >188 kDa
UniProt
Q93009
ID UBP7_HUMAN Reviewed; 1102 AA.
AC Q93009; A6NMY8;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 04-NOV-2008, sequence version 2.
DT 22-JAN-2014, entry version 151.
DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase 7;
DE EC=3.4.19.12;
DE AltName: Full=Deubiquitinating enzyme 7;
DE AltName: Full=Herpesvirus-associated ubiquitin-specific protease;
DE AltName: Full=Ubiquitin thioesterase 7;
DE AltName: Full=Ubiquitin-specific-processing protease 7;
GN Name=USP7; Synonyms=HAUSP;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Mammary cancer;
RX PubMed=9034339; DOI=10.1093/emboj/16.3.566;
RA Everett R.D., Meredith M., Orr A., Cross A., Kathoria M.,
RA Parkinson J.;
RT "A novel ubiquitin-specific protease is dynamically associated with
RT the PML nuclear domain and binds to a herpesvirus regulatory
RT protein.";
RL EMBO J. 16:566-577(1997).
RN [2]
RP ERRATUM.
RX PubMed=9130697; DOI=10.1093/emboj/16.7.1519;
RA Everett R.D., Meredith M., Orr A., Cross A., Kathoria M.,
RA Parkinson J.;
RL EMBO J. 16:1519-1530(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X.,
RA Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A.,
RA Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J.,
RA Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L.,
RA Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A.,
RA Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D.,
RA Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J.,
RA Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I.,
RA Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W.,
RA Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A.,
RA Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S.,
RA Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L.,
RA Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A.,
RA Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L.,
RA Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N.,
RA Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M.,
RA Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L.,
RA Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D.,
RA Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P.,
RA Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M.,
RA Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 705-1102 (ISOFORM 1), SUBCELLULAR
RP LOCATION, AND INTERACTION WITH ATXN1.
RX PubMed=12093161; DOI=10.1006/mcne.2002.1103;
RA Hong S., Kim S.J., Ka S., Choi I., Kang S.;
RT "USP7, a ubiquitin-specific protease, interacts with ataxin-1, the
RT SCA1 gene product.";
RL Mol. Cell. Neurosci. 20:298-306(2002).
RN [6]
RP FUNCTION, INTERACTION WITH TP53, AND MUTAGENESIS OF CYS-223.
RX PubMed=11923872; DOI=10.1038/nature737;
RA Li M., Chen D., Shiloh A., Luo J., Nikolaev A.Y., Qin J., Gu W.;
RT "Deubiquitination of p53 by HAUSP is an important pathway for p53
RT stabilization.";
RL Nature 416:648-653(2002).
RN [7]
RP FUNCTION, SUBUNIT, BIOPHYSICOCHEMICAL PROPERTIES, ENZYME REGULATION,
RP AND INTERACTION WITH HERPESVIRUS 1 TRANS-ACTING TRANSCRIPTIONAL
RP PROTEIN ICP0/VMW110 AND EBV EBNA1.
RX PubMed=14506283; DOI=10.1074/jbc.M307200200;
RA Holowaty M.N., Sheng Y., Nguyen T., Arrowsmith C., Frappier L.;
RT "Protein interaction domains of the ubiquitin-specific protease,
RT USP7/HAUSP.";
RL J. Biol. Chem. 278:47753-47761(2003).
RN [8]
RP FUNCTION, INTERACTION WITH MDM2, AND MUTAGENESIS OF CYS-223.
RX PubMed=15053880; DOI=10.1016/S1097-2765(04)00157-1;
RA Li M., Brooks C.L., Kon N., Gu W.;
RT "A dynamic role of HAUSP in the p53-Mdm2 pathway.";
RL Mol. Cell 13:879-886(2004).
RN [9]
RP FUNCTION, UBIQUITINATION, AND INTERACTION WITH HERPESVIRUS 1
RP TRANS-ACTING TRANSCRIPTIONAL PROTEIN ICP0/VMW110.
RX PubMed=16160161; DOI=10.1128/JVI.79.19.12342-12354.2005;
RA Boutell C., Canning M., Orr A., Everett R.D.;
RT "Reciprocal activities between herpes simplex virus type 1 regulatory
RT protein ICP0, a ubiquitin E3 ligase, and ubiquitin-specific protease
RT USP7.";
RL J. Virol. 79:12342-12354(2005).
RN [10]
RP IDENTIFICATION IN A COMPLEX WITH DAXX AND MDM2, INTERACTION WITH DAXX,
RP AND SUBCELLULAR LOCATION.
RX PubMed=16845383; DOI=10.1038/ncb1442;
RA Tang J., Qu L.K., Zhang J., Wang W., Michaelson J.S., Degenhardt Y.Y.,
RA El-Deiry W.S., Yang X.;
RT "Critical role for Daxx in regulating Mdm2.";
RL Nat. Cell Biol. 8:855-862(2006).
RN [11]
RP FUNCTION, INTERACTION WITH FOXO4, AND MUTAGENESIS OF CYS-223.
RX PubMed=16964248; DOI=10.1038/ncb1469;
RA van der Horst A., de Vries-Smits A.M., Brenkman A.B., van Triest M.H.,
RA van den Broek N., Colland F., Maurice M.M., Burgering B.M.;
RT "FOXO4 transcriptional activity is regulated by monoubiquitination and
RT USP7/HAUSP.";
RL Nat. Cell Biol. 8:1064-1073(2006).
RN [12]
RP SUBUNIT, PHOSPHORYLATION AT SER-18 AND SER-963, UBIQUITINATION AT
RP LYS-869, SUBCELLULAR LOCATION, AND MASS SPECTROMETRY.
RX PubMed=17651432; DOI=10.1111/j.1742-4658.2007.05952.x;
RA Fernandez-Montalvan A., Bouwmeester T., Joberty G., Mader R.,
RA Mahnke M., Pierrat B., Schlaeppi J.M., Worpenberg S., Gerhartz B.;
RT "Biochemical characterization of USP7 reveals post-translational
RT modification sites and structural requirements for substrate
RT processing and subcellular localization.";
RL FEBS J. 274:4256-4270(2007).
RN [13]
RP IDENTIFICATION IN A COMPLEX WITH DAXX; RASSF1 AND MDM2, AND
RP INTERACTION WITH DAXX AND MDM2.
RX PubMed=18566590; DOI=10.1038/emboj.2008.115;
RA Song M.S., Song S.J., Kim S.Y., Oh H.J., Lim D.S.;
RT "The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by
RT disrupting the MDM2-DAXX-HAUSP complex.";
RL EMBO J. 27:1863-1874(2008).
RN [14]
RP INTERACTION WITH UBXN6.
RX PubMed=18768758; DOI=10.1091/mbc.E08-01-0067;
RA Zweitzig D.R., Shcherbik N., Haines D.S.;
RT "AAA ATPase p97 and adaptor UBXD1 suppress MDM2 ubiquitination and
RT degradation and promote constitutive p53 turnover.";
RL Mol. Biol. Cell 19:5029-5029(2008).
RN [15]
RP FUNCTION, INTERACTION WITH PTEN, MUTAGENESIS OF CYS-223, SUBCELLULAR
RP LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=18716620; DOI=10.1038/nature07290;
RA Song M.S., Salmena L., Carracedo A., Egia A., Lo-Coco F.,
RA Teruya-Feldstein J., Pandolfi P.P.;
RT "The deubiquitinylation and localization of PTEN are regulated by a
RT HAUSP-PML network.";
RL Nature 455:813-817(2008).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-18 AND SER-963, AND MASS
RP SPECTROMETRY.
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 [17]
RP FUNCTION, INTERACTION WITH HERPESVIRUS 1 TRANS-ACTING TRANSCRIPTIONAL
RP PROTEIN ICP0/VMW110, SUBCELLULAR LOCATION, MASS SPECTROMETRY, AND
RP ALTERNATIVE SPLICING (ISOFORM 2).
RX PubMed=18590780; DOI=10.1016/j.virusres.2008.05.017;
RA Antrobus R., Boutell C.;
RT "Identification of a novel higher molecular weight isoform of
RT USP7/HAUSP that interacts with the Herpes simplex virus type-1
RT immediate early protein ICP0.";
RL Virus Res. 137:64-71(2008).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [19]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-869; LYS-1084 AND LYS-1096,
RP AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [20]
RP FUNCTION.
RX PubMed=20153724; DOI=10.1016/j.bbrc.2010.02.051;
RA Tang J., Qu L., Pang M., Yang X.;
RT "Daxx is reciprocally regulated by Mdm2 and Hausp.";
RL Biochem. Biophys. Res. Commun. 393:542-545(2010).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-18, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [22]
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.,
RA Buerckstuemmer T., 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 [23]
RP INTERACTION WITH TSPYL5.
RX PubMed=21170034; DOI=10.1038/ncb2142;
RA Epping M.T., Meijer L.A., Krijgsman O., Bos J.L., Pandolfi P.P.,
RA Bernards R.;
RT "TSPYL5 suppresses p53 levels and function by physical interaction
RT with USP7.";
RL Nat. Cell Biol. 13:102-108(2011).
RN [24]
RP FUNCTION, INTERACTION WITH DNMT1 AND UHRF1, AND MUTAGENESIS OF
RP CYS-223.
RX PubMed=21745816; DOI=10.1093/nar/gkr528;
RA Felle M., Joppien S., Nemeth A., Diermeier S., Thalhammer V.,
RA Dobner T., Kremmer E., Kappler R., Langst G.;
RT "The USP7/Dnmt1 complex stimulates the DNA methylation activity of
RT Dnmt1 and regulates the stability of UHRF1.";
RL Nucleic Acids Res. 39:8355-8365(2011).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-18, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [26]
RP FUNCTION, INTERACTION WITH UHRF1, AND MUTAGENESIS OF CYS-223.
RX PubMed=22411829; DOI=10.1073/pnas.1116349109;
RA Ma H., Chen H., Guo X., Wang Z., Sowa M.E., Zheng L., Hu S., Zeng P.,
RA Guo R., Diao J., Lan F., Harper J.W., Shi Y.G., Xu Y., Shi Y.;
RT "M phase phosphorylation of the epigenetic regulator UHRF1 regulates
RT its physical association with the deubiquitylase USP7 and stability.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:4828-4833(2012).
RN [27]
RP FUNCTION, AND LINKAGE SPECIFICITY.
RX PubMed=22689415; DOI=10.1002/cbic.201200261;
RA Iphofer A., Kummer A., Nimtz M., Ritter A., Arnold T., Frank R.,
RA van den Heuvel J., Kessler B.M., Jansch L., Franke R.;
RT "Profiling ubiquitin linkage specificities of deubiquitinating enzymes
RT with branched ubiquitin isopeptide probes.";
RL ChemBioChem 13:1416-1420(2012).
RN [28]
RP INTERACTION WITH MEX3C.
RX PubMed=22863774; DOI=10.1038/emboj.2012.218;
RA Cano F., Bye H., Duncan L.M., Buchet-Poyau K., Billaud M., Wills M.R.,
RA Lehner P.J.;
RT "The RNA-binding E3 ubiquitin ligase MEX-3C links ubiquitination with
RT MHC-I mRNA degradation.";
RL EMBO J. 31:3596-3606(2012).
RN [29]
RP FUNCTION, AND INTERACTION WITH UVSSA.
RX PubMed=22466611; DOI=10.1038/ng.2230;
RA Schwertman P., Lagarou A., Dekkers D.H., Raams A., van der Hoek A.C.,
RA Laffeber C., Hoeijmakers J.H., Demmers J.A., Fousteri M.,
RA Vermeulen W., Marteijn J.A.;
RT "UV-sensitive syndrome protein UVSSA recruits USP7 to regulate
RT transcription-coupled repair.";
RL Nat. Genet. 44:598-602(2012).
RN [30]
RP FUNCTION, AND INTERACTION WITH UVSSA.
RX PubMed=22466612; DOI=10.1038/ng.2228;
RA Zhang X., Horibata K., Saijo M., Ishigami C., Ukai A., Kanno S.I.,
RA Tahara H., Neilan E.G., Honma M., Nohmi T., Yasui A., Tanaka K.;
RT "Mutations in UVSSA cause UV-sensitive syndrome and destabilize ERCC6
RT in transcription-coupled DNA repair.";
RL Nat. Genet. 44:593-597(2012).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 208-560 IN COMPLEX WITH
RP UBIQUITIN, MUTAGENESIS OF CYS-223; HIS-456 AND HIS-464, AND
RP INTERACTION WITH TP53.
RX PubMed=12507430; DOI=10.1016/S0092-8674(02)01199-6;
RA Hu M., Li P., Li M., Li W., Yao T., Wu J.-W., Gu W., Cohen R.E.,
RA Shi Y.;
RT "Crystal structure of a UBP-family deubiquitinating enzyme in
RT isolation and in complex with ubiquitin aldehyde.";
RL Cell 111:1041-1054(2002).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 54-205 IN COMPLEX WITH EBNA1,
RP AND INTERACTION WITH EBV EBNA1.
RX PubMed=15808506; DOI=10.1016/j.molcel.2005.02.029;
RA Saridakis V., Sheng Y., Sarkari F., Holowaty M.N., Shire K.,
RA Nguyen T., Zhang R.G., Liao J., Lee W., Edwards A.M., Arrowsmith C.H.,
RA Frappier L.;
RT "Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-
RT Barr nuclear antigen 1 implications for EBV-mediated
RT immortalization.";
RL Mol. Cell 18:25-36(2005).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 43-560 IN COMPLEX WITH TP53
RP AND MDM2, AND INTERACTION WITH TP53 AND MDM2.
RX PubMed=16402859; DOI=10.1371/journal.pbio.0040027;
RA Hu M., Gu L., Li M., Jeffrey P.D., Gu W., Shi Y.;
RT "Structural basis of competitive recognition of p53 and MDM2 by
RT HAUSP/USP7: implications for the regulation of the p53-MDM2 pathway.";
RL PLoS Biol. 4:228-239(2006).
RN [34]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 54-205 IN COMPLEX WITH TP53
RP AND MDM2, INTERACTION WITH TP53 AND MDM2, AND MUTAGENESIS OF ASP-164
RP AND TRP-165.
RX PubMed=16474402; DOI=10.1038/nsmb1067;
RA Sheng Y., Saridakis V., Sarkari F., Duan S., Wu T., Arrowsmith C.H.,
RA Frappier L.;
RT "Molecular recognition of p53 and MDM2 by USP7/HAUSP.";
RL Nat. Struct. Mol. Biol. 13:285-291(2006).
CC -!- FUNCTION: Hydrolase that deubiquitinates target proteins such as
CC FOXO4, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN and DAXX.
CC Together with DAXX, prevents MDM2 self-ubiquitination and enhances
CC the E3 ligase activity of MDM2 towards p53/TP53, thereby promoting
CC p53/TP53 ubiquitination and proteasomal degradation.
CC Deubiquitinates p53/TP53 and MDM2 and strongly stabilizes p53/TP53
CC even in the presence of excess MDM2, and also induces p53/TP53-
CC dependent cell growth repression and apoptosis. Deubiquitination
CC of FOXO4 in presence of hydrogen peroxide is not dependent on
CC p53/TP53 and inhibits FOXO4-induced transcriptional activity. In
CC association with DAXX, is involved in the deubiquitination and
CC translocation of PTEN from the nucleus to the cytoplasm, both
CC processes that are counteracted by PML. Involved in cell
CC proliferation during early embryonic development. Involved in
CC transcription-coupled nucleotide excision repair (TC-NER) in
CC response to UV damage: recruited to DNA damage sites following
CC interaction with KIAA1530/UVSSA and promotes deubiquitination of
CC ERCC6, preventing UV-induced degradation of ERCC6. Contributes to
CC the overall stabilization and trans-activation capability of the
CC herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110
CC during HSV-1 infection. Involved in maintenance of DNA methylation
CC via its interaction with UHRF1 and DNMT1: acts by mediating
CC deubiquitination of UHRF1 and DNMT1, preventing their degradation
CC and promoting DNA methylation by DNMT1. Exhibits a preference
CC towards 'Lys-48'-linked Ubiquitin chains.
CC -!- CATALYTIC ACTIVITY: Thiol-dependent hydrolysis of ester,
CC thioester, amide, peptide and isopeptide bonds formed by the C-
CC terminal Gly of ubiquitin (a 76-residue protein attached to
CC proteins as an intracellular targeting signal).
CC -!- ENZYME REGULATION: Inhibited by N-ethyl-maleimide (NEM) and
CC divalent cations. Tolerates high concentrations of NaCl but is
CC inhibited at concentrations of 195 mM and higher.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC pH dependence:
CC Active from pH 7.0 to 9.5;
CC -!- SUBUNIT: Monomer. Homodimer. Part of a complex with DAXX, MDM2,
CC RASSF1 and USP7. Part of a complex with DAXX, MDM2 and USP7.
CC Interacts with MDM2; the interaction is independent of p53/TP53.
CC Interacts with DAXX; the interaction is direct and independent of
CC MDM2 and p53/TP53. Interacts with FOXO4; the interaction is
CC enhanced in presence of hydrogen peroxide and occurs independently
CC of p53/TP53. Interacts with p53/TP53; the interaction is enhanced
CC in response to DNA damage; the interaction is impaired by TSPYL5.
CC Interacts with PTEN; the interaction is direct. Interacts with
CC UBXN6. Interacts with ATXN1 and the strength of interaction is
CC influenced by the length of the poly-Gln region in ATXN1. A weaker
CC interaction seen with mutants having longer poly-Gln regions.
CC Interacts with KIAA1530/UVSSA. Isoform 1 and isoform 2 interact
CC with herpesvirus 1 trans-acting transcriptional protein
CC ICP0/VMW110. Interacts with Epstein-Barr virus EBNA1. EBNA1 shows
CC a 10-fold higher affinity than p53/TP53 and can compete with it
CC for USP7 binding. Binding to ICP0/VMW110 may modulate the
CC substrate specificity or activity of USP7 to stabilize viral
CC proteins. Interacts with MEX3C and antagonizes its ability to
CC degrade mRNA. Interacts with DNMT1 and UHRF1.
CC -!- INTERACTION:
CC P35226:BMI1; NbExp=7; IntAct=EBI-302474, EBI-2341576;
CC Q9HC52:CBX8; NbExp=7; IntAct=EBI-302474, EBI-712912;
CC Q9UER7:DAXX; NbExp=13; IntAct=EBI-302474, EBI-77321;
CC P03211:EBNA1 (xeno); NbExp=4; IntAct=EBI-302474, EBI-996522;
CC P21145:MAL; NbExp=3; IntAct=EBI-302474, EBI-3932027;
CC Q00987:MDM2; NbExp=18; IntAct=EBI-302474, EBI-389668;
CC O15151:MDM4; NbExp=15; IntAct=EBI-302474, EBI-398437;
CC O35618:Mdm4 (xeno); NbExp=4; IntAct=EBI-302474, EBI-2603376;
CC Q5U5Q3:MEX3C; NbExp=3; IntAct=EBI-302474, EBI-2864451;
CC Q99836:MYD88; NbExp=3; IntAct=EBI-302474, EBI-447677;
CC P35227:PCGF2; NbExp=5; IntAct=EBI-302474, EBI-2129767;
CC Q06587:RING1; NbExp=4; IntAct=EBI-302474, EBI-752313;
CC Q99496:RNF2; NbExp=4; IntAct=EBI-302474, EBI-722416;
CC P84022:SMAD3; NbExp=2; IntAct=EBI-302474, EBI-347161;
CC Q99426:TBCB; NbExp=2; IntAct=EBI-302474, EBI-764356;
CC P04637:TP53; NbExp=17; IntAct=EBI-302474, EBI-366083;
CC Q86VY4:TSPYL5; NbExp=4; IntAct=EBI-302474, EBI-3436472;
CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Nucleus, PML body.
CC Note=Present in a minority of ND10 nuclear bodies. Association
CC with ICP0/VMW110 at early times of infection leads to an increased
CC proportion of USP7-containing ND10. Colocalizes with ATXN1 in the
CC nucleus. Colocalized with DAXX in speckled structures. Colocalized
CC with PML and PTEN in promyelocytic leukemia protein (PML) nuclear
CC bodies.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q93009-1; Sequence=Displayed;
CC Name=2; Synonyms=USP7 beta;
CC IsoId=Q93009-2; Sequence=Not described;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Widely expressed. Overexpressed in prostate
CC cancer.
CC -!- DOMAIN: The C-terminus plays a role in its oligomerization (By
CC similarity).
CC -!- PTM: Isoform 1: Phosphorylated. Isoform 1 is phosphorylated at
CC positions Ser-18 and Ser-963. Isoform 2: Not phosphorylated.
CC -!- PTM: Isoform 1: Polyneddylated. Isoform 2: Not Polyneddylated.
CC -!- PTM: Isoform 1 and isoform 2: Not sumoylated.
CC -!- PTM: Isoform 1 and isoform 2: Polyubiquitinated by herpesvirus 1
CC trans-acting transcriptional protein ICP0/VMW110; leading to its
CC subsequent proteasomal degradation. Isoform 1: Ubiquitinated at
CC Lys-869.
CC -!- SIMILARITY: Belongs to the peptidase C19 family.
CC -!- SIMILARITY: Contains 1 MATH domain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org//Genes/USP7ID42773ch16p13.html";
CC -----------------------------------------------------------------------
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DR EMBL; Z72499; CAA96580.1; -; mRNA.
DR EMBL; AC022167; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471112; EAW85194.1; -; Genomic_DNA.
DR RefSeq; NP_003461.2; NM_003470.2.
DR UniGene; Hs.386939; -.
DR PDB; 1NB8; X-ray; 2.30 A; A/B=208-560.
DR PDB; 1NBF; X-ray; 2.30 A; A/B/E=208-560.
DR PDB; 1YY6; X-ray; 1.70 A; A=54-205.
DR PDB; 1YZE; X-ray; 2.00 A; A/B/C=54-205.
DR PDB; 2F1W; X-ray; 1.65 A; A=53-206.
DR PDB; 2F1X; X-ray; 2.30 A; A/B=53-200.
DR PDB; 2F1Y; X-ray; 1.70 A; A=53-198.
DR PDB; 2F1Z; X-ray; 3.20 A; A/B=43-560.
DR PDB; 2FOJ; X-ray; 1.60 A; A=54-205.
DR PDB; 2FOO; X-ray; 2.20 A; A=54-205.
DR PDB; 2FOP; X-ray; 2.10 A; A=54-205.
DR PDB; 2KVR; NMR; -; A=537-664.
DR PDB; 2XXN; X-ray; 1.60 A; A=63-205.
DR PDB; 2YLM; X-ray; 2.70 A; A=560-1084.
DR PDB; 3MQR; X-ray; 1.80 A; A=54-205.
DR PDB; 3MQS; X-ray; 2.40 A; C=54-205.
DR PDB; 4JJQ; X-ray; 1.95 A; A=54-205.
DR PDB; 4KG9; X-ray; 1.70 A; A=54-205.
DR PDBsum; 1NB8; -.
DR PDBsum; 1NBF; -.
DR PDBsum; 1YY6; -.
DR PDBsum; 1YZE; -.
DR PDBsum; 2F1W; -.
DR PDBsum; 2F1X; -.
DR PDBsum; 2F1Y; -.
DR PDBsum; 2F1Z; -.
DR PDBsum; 2FOJ; -.
DR PDBsum; 2FOO; -.
DR PDBsum; 2FOP; -.
DR PDBsum; 2KVR; -.
DR PDBsum; 2XXN; -.
DR PDBsum; 2YLM; -.
DR PDBsum; 3MQR; -.
DR PDBsum; 3MQS; -.
DR PDBsum; 4JJQ; -.
DR PDBsum; 4KG9; -.
DR ProteinModelPortal; Q93009; -.
DR SMR; Q93009; 63-554, 560-1083.
DR DIP; DIP-29053N; -.
DR IntAct; Q93009; 104.
DR MINT; MINT-234628; -.
DR STRING; 9606.ENSP00000343535; -.
DR ChEMBL; CHEMBL2157850; -.
DR MEROPS; C19.016; -.
DR PhosphoSite; Q93009; -.
DR DMDM; 212276477; -.
DR PaxDb; Q93009; -.
DR PRIDE; Q93009; -.
DR DNASU; 7874; -.
DR Ensembl; ENST00000344836; ENSP00000343535; ENSG00000187555.
DR GeneID; 7874; -.
DR KEGG; hsa:7874; -.
DR UCSC; uc002czl.2; human.
DR CTD; 7874; -.
DR GeneCards; GC16M008985; -.
DR H-InvDB; HIX0038590; -.
DR HGNC; HGNC:12630; USP7.
DR HPA; CAB008108; -.
DR HPA; HPA015641; -.
DR MIM; 602519; gene.
DR neXtProt; NX_Q93009; -.
DR PharmGKB; PA37255; -.
DR eggNOG; COG5077; -.
DR HOGENOM; HOG000160240; -.
DR HOVERGEN; HBG018029; -.
DR KO; K11838; -.
DR OMA; MCERAGF; -.
DR OrthoDB; EOG75B84G; -.
DR SignaLink; Q93009; -.
DR EvolutionaryTrace; Q93009; -.
DR GeneWiki; USP7; -.
DR GenomeRNAi; 7874; -.
DR NextBio; 30332; -.
DR PRO; PR:Q93009; -.
DR ArrayExpress; Q93009; -.
DR Bgee; Q93009; -.
DR CleanEx; HS_USP7; -.
DR Genevestigator; Q93009; -.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0016605; C:PML body; IEA:UniProtKB-SubCell.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IMP:UniProtKB.
DR GO; GO:0004843; F:deubiquitinase activity; IDA:UniProtKB.
DR GO; GO:0002039; F:p53 binding; IDA:UniProtKB.
DR GO; GO:0004221; F:ubiquitin thiolesterase activity; IDA:UniProtKB.
DR GO; GO:0010216; P:maintenance of DNA methylation; IMP:UniProtKB.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0007275; P:multicellular organismal development; IEA:UniProtKB-KW.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IDA:UniProtKB.
DR GO; GO:0016579; P:protein deubiquitination; IDA:UniProtKB.
DR GO; GO:0006283; P:transcription-coupled nucleotide-excision repair; IMP:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IEA:InterPro.
DR InterPro; IPR002083; MATH.
DR InterPro; IPR018200; Pept_C19ubi-hydrolase_C_CS.
DR InterPro; IPR001394; Peptidase_C19/C67.
DR InterPro; IPR008974; TRAF-like.
DR InterPro; IPR024729; USP7_ICP0-binding_dom.
DR Pfam; PF00917; MATH; 1.
DR Pfam; PF00443; UCH; 1.
DR Pfam; PF12436; USP7_ICP0_bdg; 1.
DR SMART; SM00061; MATH; 1.
DR SUPFAM; SSF49599; SSF49599; 1.
DR PROSITE; PS50144; MATH; 1.
DR PROSITE; PS00972; UCH_2_1; 1.
DR PROSITE; PS00973; UCH_2_2; 1.
DR PROSITE; PS50235; UCH_2_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Cytoplasm; Developmental protein; Direct protein sequencing;
KW DNA damage; DNA repair; Host-virus interaction; Hydrolase;
KW Isopeptide bond; Nucleus; Phosphoprotein; Protease;
KW Reference proteome; Thiol protease; Ubl conjugation;
KW Ubl conjugation pathway.
FT CHAIN 1 1102 Ubiquitin carboxyl-terminal hydrolase 7.
FT /FTId=PRO_0000080626.
FT DOMAIN 68 195 MATH.
FT REGION 1 208 Interaction with TSPYL5.
FT REGION 53 208 Interaction with p53/TP53, MDM2 and
FT EBNA1.
FT REGION 70 205 Necessary for nuclear localization.
FT REGION 622 801 Interaction with ICP0/VMW110.
FT COMPBIAS 4 10 Poly-Gln.
FT ACT_SITE 223 223 Nucleophile.
FT ACT_SITE 464 464 Proton acceptor (Probable).
FT MOD_RES 18 18 Phosphoserine.
FT MOD_RES 869 869 N6-acetyllysine; alternate.
FT MOD_RES 963 963 Phosphoserine.
FT MOD_RES 1084 1084 N6-acetyllysine.
FT MOD_RES 1096 1096 N6-acetyllysine.
FT CROSSLNK 869 869 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin);
FT alternate.
FT MUTAGEN 164 164 D->A: Decreased binding to p53/TP53 and
FT MDM2.
FT MUTAGEN 165 165 W->A: Loss of binding to p53/TP53 and
FT MDM2.
FT MUTAGEN 223 223 C->A: Complete loss of activity.
FT Localized in the nucleus and does not
FT inhibit FOXO4-dependent transcriptional
FT activity.
FT MUTAGEN 223 223 C->S: No effect on p53/TP53 and PTEN
FT binding but is defective in
FT deubiquitinating p53/TP53 and PTEN.
FT MUTAGEN 456 456 H->A: Complete loss of activity.
FT MUTAGEN 464 464 H->A: Complete loss of activity.
FT CONFLICT 201 201 H -> I (in Ref. 1; AA sequence).
FT CONFLICT 205 205 W -> P (in Ref. 1; AA sequence).
FT CONFLICT 207 207 S -> Q (in Ref. 1; AA sequence).
FT CONFLICT 1045 1045 M -> T (in Ref. 1; CAA96580).
FT CONFLICT 1066 1066 Q -> T (in Ref. 1; AA sequence).
FT STRAND 67 77
FT HELIX 78 80
FT STRAND 90 92
FT STRAND 95 104
FT STRAND 113 122
FT STRAND 131 140
FT HELIX 146 148
FT STRAND 150 159
FT HELIX 160 162
FT STRAND 164 172
FT HELIX 173 176
FT TURN 179 181
FT STRAND 182 185
FT STRAND 188 197
FT STRAND 201 203
FT STRAND 210 212
FT TURN 221 224
FT HELIX 225 233
FT HELIX 236 243
FT TURN 252 254
FT HELIX 256 269
FT HELIX 277 283
FT TURN 288 293
FT HELIX 296 310
FT TURN 311 313
FT TURN 315 318
FT HELIX 319 324
FT STRAND 326 337
FT STRAND 340 348
FT STRAND 350 352
FT HELIX 360 367
FT STRAND 371 373
FT TURN 375 377
FT HELIX 382 384
FT STRAND 389 396
FT STRAND 400 406
FT STRAND 409 412
FT TURN 413 416
FT STRAND 417 420
FT STRAND 429 432
FT HELIX 434 436
FT STRAND 437 439
FT STRAND 447 459
FT STRAND 465 469
FT STRAND 473 475
FT STRAND 478 481
FT STRAND 484 487
FT HELIX 490 493
FT HELIX 495 497
FT TURN 507 510
FT STRAND 511 520
FT TURN 521 523
FT HELIX 524 527
FT HELIX 533 535
FT HELIX 538 552
FT HELIX 561 563
FT STRAND 564 571
FT HELIX 572 575
FT STRAND 580 583
FT TURN 586 588
FT STRAND 592 597
FT HELIX 602 613
FT HELIX 617 619
FT STRAND 620 627
FT STRAND 633 635
FT HELIX 640 643
FT HELIX 648 652
FT STRAND 656 664
FT HELIX 667 670
FT TURN 671 673
FT TURN 681 683
FT STRAND 684 693
FT TURN 694 697
FT STRAND 698 708
FT HELIX 713 715
FT HELIX 717 724
FT STRAND 732 739
FT STRAND 742 745
FT STRAND 749 752
FT HELIX 753 756
FT STRAND 764 770
FT HELIX 773 777
FT STRAND 778 780
FT HELIX 783 792
FT STRAND 793 800
FT STRAND 809 814
FT HELIX 819 830
FT HELIX 834 836
FT STRAND 837 840
FT HELIX 861 864
FT STRAND 870 872
FT STRAND 875 880
FT HELIX 885 889
FT STRAND 894 899
FT STRAND 905 910
FT HELIX 918 926
FT STRAND 939 945
FT STRAND 948 953
FT HELIX 959 961
FT STRAND 969 974
FT HELIX 977 979
FT TURN 984 986
FT STRAND 987 998
FT STRAND 1002 1012
FT HELIX 1017 1028
FT HELIX 1032 1035
FT STRAND 1039 1044
FT STRAND 1047 1050
FT TURN 1053 1055
FT HELIX 1060 1062
FT STRAND 1070 1072
FT STRAND 1076 1080
SQ SEQUENCE 1102 AA; 128302 MW; F1A5A5C421396E45 CRC64;
MNHQQQQQQQ KAGEQQLSEP EDMEMEAGDT DDPPRITQNP VINGNVALSD GHNTAEEDME
DDTSWRSEAT FQFTVERFSR LSESVLSPPC FVRNLPWKIM VMPRFYPDRP HQKSVGFFLQ
CNAESDSTSW SCHAQAVLKI INYRDDEKSF SRRISHLFFH KENDWGFSNF MAWSEVTDPE
KGFIDDDKVT FEVFVQADAP HGVAWDSKKH TGYVGLKNQG ATCYMNSLLQ TLFFTNQLRK
AVYMMPTEGD DSSKSVPLAL QRVFYELQHS DKPVGTKKLT KSFGWETLDS FMQHDVQELC
RVLLDNVENK MKGTCVEGTI PKLFRGKMVS YIQCKEVDYR SDRREDYYDI QLSIKGKKNI
FESFVDYVAV EQLDGDNKYD AGEHGLQEAE KGVKFLTLPP VLHLQLMRFM YDPQTDQNIK
INDRFEFPEQ LPLDEFLQKT DPKDPANYIL HAVLVHSGDN HGGHYVVYLN PKGDGKWCKF
DDDVVSRCTK EEAIEHNYGG HDDDLSVRHC TNAYMLVYIR ESKLSEVLQA VTDHDIPQQL
VERLQEEKRI EAQKRKERQE AHLYMQVQIV AEDQFCGHQG NDMYDEEKVK YTVFKVLKNS
SLAEFVQSLS QTMGFPQDQI RLWPMQARSN GTKRPAMLDN EADGNKTMIE LSDNENPWTI
FLETVDPELA ASGATLPKFD KDHDVMLFLK MYDPKTRSLN YCGHIYTPIS CKIRDLLPVM
CDRAGFIQDT SLILYEEVKP NLTERIQDYD VSLDKALDEL MDGDIIVFQK DDPENDNSEL
PTAKEYFRDL YHRVDVIFCD KTIPNDPGFV VTLSNRMNYF QVAKTVAQRL NTDPMLLQFF
KSQGYRDGPG NPLRHNYEGT LRDLLQFFKP RQPKKLYYQQ LKMKITDFEN RRSFKCIWLN
SQFREEEITL YPDKHGCVRD LLEECKKAVE LGEKASGKLR LLEIVSYKII GVHQEDELLE
CLSPATSRTF RIEEIPLDQV DIDKENEMLV TVAHFHKEVF GTFGIPFLLR IHQGEHFREV
MKRIQSLLDI QEKEFEKFKF AIVMMGRHQY INEDEYEVNL KDFEPQPGNM SHPRPWLGLD
HFNKAPKRSR YTYLEKAIKI HN
//
ID UBP7_HUMAN Reviewed; 1102 AA.
AC Q93009; A6NMY8;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 04-NOV-2008, sequence version 2.
DT 22-JAN-2014, entry version 151.
DE RecName: Full=Ubiquitin carboxyl-terminal hydrolase 7;
DE EC=3.4.19.12;
DE AltName: Full=Deubiquitinating enzyme 7;
DE AltName: Full=Herpesvirus-associated ubiquitin-specific protease;
DE AltName: Full=Ubiquitin thioesterase 7;
DE AltName: Full=Ubiquitin-specific-processing protease 7;
GN Name=USP7; Synonyms=HAUSP;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Mammary cancer;
RX PubMed=9034339; DOI=10.1093/emboj/16.3.566;
RA Everett R.D., Meredith M., Orr A., Cross A., Kathoria M.,
RA Parkinson J.;
RT "A novel ubiquitin-specific protease is dynamically associated with
RT the PML nuclear domain and binds to a herpesvirus regulatory
RT protein.";
RL EMBO J. 16:566-577(1997).
RN [2]
RP ERRATUM.
RX PubMed=9130697; DOI=10.1093/emboj/16.7.1519;
RA Everett R.D., Meredith M., Orr A., Cross A., Kathoria M.,
RA Parkinson J.;
RL EMBO J. 16:1519-1530(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X.,
RA Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A.,
RA Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J.,
RA Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L.,
RA Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A.,
RA Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D.,
RA Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J.,
RA Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I.,
RA Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W.,
RA Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A.,
RA Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S.,
RA Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L.,
RA Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A.,
RA Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L.,
RA Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N.,
RA Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M.,
RA Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L.,
RA Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D.,
RA Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P.,
RA Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M.,
RA Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 705-1102 (ISOFORM 1), SUBCELLULAR
RP LOCATION, AND INTERACTION WITH ATXN1.
RX PubMed=12093161; DOI=10.1006/mcne.2002.1103;
RA Hong S., Kim S.J., Ka S., Choi I., Kang S.;
RT "USP7, a ubiquitin-specific protease, interacts with ataxin-1, the
RT SCA1 gene product.";
RL Mol. Cell. Neurosci. 20:298-306(2002).
RN [6]
RP FUNCTION, INTERACTION WITH TP53, AND MUTAGENESIS OF CYS-223.
RX PubMed=11923872; DOI=10.1038/nature737;
RA Li M., Chen D., Shiloh A., Luo J., Nikolaev A.Y., Qin J., Gu W.;
RT "Deubiquitination of p53 by HAUSP is an important pathway for p53
RT stabilization.";
RL Nature 416:648-653(2002).
RN [7]
RP FUNCTION, SUBUNIT, BIOPHYSICOCHEMICAL PROPERTIES, ENZYME REGULATION,
RP AND INTERACTION WITH HERPESVIRUS 1 TRANS-ACTING TRANSCRIPTIONAL
RP PROTEIN ICP0/VMW110 AND EBV EBNA1.
RX PubMed=14506283; DOI=10.1074/jbc.M307200200;
RA Holowaty M.N., Sheng Y., Nguyen T., Arrowsmith C., Frappier L.;
RT "Protein interaction domains of the ubiquitin-specific protease,
RT USP7/HAUSP.";
RL J. Biol. Chem. 278:47753-47761(2003).
RN [8]
RP FUNCTION, INTERACTION WITH MDM2, AND MUTAGENESIS OF CYS-223.
RX PubMed=15053880; DOI=10.1016/S1097-2765(04)00157-1;
RA Li M., Brooks C.L., Kon N., Gu W.;
RT "A dynamic role of HAUSP in the p53-Mdm2 pathway.";
RL Mol. Cell 13:879-886(2004).
RN [9]
RP FUNCTION, UBIQUITINATION, AND INTERACTION WITH HERPESVIRUS 1
RP TRANS-ACTING TRANSCRIPTIONAL PROTEIN ICP0/VMW110.
RX PubMed=16160161; DOI=10.1128/JVI.79.19.12342-12354.2005;
RA Boutell C., Canning M., Orr A., Everett R.D.;
RT "Reciprocal activities between herpes simplex virus type 1 regulatory
RT protein ICP0, a ubiquitin E3 ligase, and ubiquitin-specific protease
RT USP7.";
RL J. Virol. 79:12342-12354(2005).
RN [10]
RP IDENTIFICATION IN A COMPLEX WITH DAXX AND MDM2, INTERACTION WITH DAXX,
RP AND SUBCELLULAR LOCATION.
RX PubMed=16845383; DOI=10.1038/ncb1442;
RA Tang J., Qu L.K., Zhang J., Wang W., Michaelson J.S., Degenhardt Y.Y.,
RA El-Deiry W.S., Yang X.;
RT "Critical role for Daxx in regulating Mdm2.";
RL Nat. Cell Biol. 8:855-862(2006).
RN [11]
RP FUNCTION, INTERACTION WITH FOXO4, AND MUTAGENESIS OF CYS-223.
RX PubMed=16964248; DOI=10.1038/ncb1469;
RA van der Horst A., de Vries-Smits A.M., Brenkman A.B., van Triest M.H.,
RA van den Broek N., Colland F., Maurice M.M., Burgering B.M.;
RT "FOXO4 transcriptional activity is regulated by monoubiquitination and
RT USP7/HAUSP.";
RL Nat. Cell Biol. 8:1064-1073(2006).
RN [12]
RP SUBUNIT, PHOSPHORYLATION AT SER-18 AND SER-963, UBIQUITINATION AT
RP LYS-869, SUBCELLULAR LOCATION, AND MASS SPECTROMETRY.
RX PubMed=17651432; DOI=10.1111/j.1742-4658.2007.05952.x;
RA Fernandez-Montalvan A., Bouwmeester T., Joberty G., Mader R.,
RA Mahnke M., Pierrat B., Schlaeppi J.M., Worpenberg S., Gerhartz B.;
RT "Biochemical characterization of USP7 reveals post-translational
RT modification sites and structural requirements for substrate
RT processing and subcellular localization.";
RL FEBS J. 274:4256-4270(2007).
RN [13]
RP IDENTIFICATION IN A COMPLEX WITH DAXX; RASSF1 AND MDM2, AND
RP INTERACTION WITH DAXX AND MDM2.
RX PubMed=18566590; DOI=10.1038/emboj.2008.115;
RA Song M.S., Song S.J., Kim S.Y., Oh H.J., Lim D.S.;
RT "The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by
RT disrupting the MDM2-DAXX-HAUSP complex.";
RL EMBO J. 27:1863-1874(2008).
RN [14]
RP INTERACTION WITH UBXN6.
RX PubMed=18768758; DOI=10.1091/mbc.E08-01-0067;
RA Zweitzig D.R., Shcherbik N., Haines D.S.;
RT "AAA ATPase p97 and adaptor UBXD1 suppress MDM2 ubiquitination and
RT degradation and promote constitutive p53 turnover.";
RL Mol. Biol. Cell 19:5029-5029(2008).
RN [15]
RP FUNCTION, INTERACTION WITH PTEN, MUTAGENESIS OF CYS-223, SUBCELLULAR
RP LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=18716620; DOI=10.1038/nature07290;
RA Song M.S., Salmena L., Carracedo A., Egia A., Lo-Coco F.,
RA Teruya-Feldstein J., Pandolfi P.P.;
RT "The deubiquitinylation and localization of PTEN are regulated by a
RT HAUSP-PML network.";
RL Nature 455:813-817(2008).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-18 AND SER-963, AND MASS
RP SPECTROMETRY.
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 [17]
RP FUNCTION, INTERACTION WITH HERPESVIRUS 1 TRANS-ACTING TRANSCRIPTIONAL
RP PROTEIN ICP0/VMW110, SUBCELLULAR LOCATION, MASS SPECTROMETRY, AND
RP ALTERNATIVE SPLICING (ISOFORM 2).
RX PubMed=18590780; DOI=10.1016/j.virusres.2008.05.017;
RA Antrobus R., Boutell C.;
RT "Identification of a novel higher molecular weight isoform of
RT USP7/HAUSP that interacts with the Herpes simplex virus type-1
RT immediate early protein ICP0.";
RL Virus Res. 137:64-71(2008).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [19]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-869; LYS-1084 AND LYS-1096,
RP AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [20]
RP FUNCTION.
RX PubMed=20153724; DOI=10.1016/j.bbrc.2010.02.051;
RA Tang J., Qu L., Pang M., Yang X.;
RT "Daxx is reciprocally regulated by Mdm2 and Hausp.";
RL Biochem. Biophys. Res. Commun. 393:542-545(2010).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-18, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [22]
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.,
RA Buerckstuemmer T., 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 [23]
RP INTERACTION WITH TSPYL5.
RX PubMed=21170034; DOI=10.1038/ncb2142;
RA Epping M.T., Meijer L.A., Krijgsman O., Bos J.L., Pandolfi P.P.,
RA Bernards R.;
RT "TSPYL5 suppresses p53 levels and function by physical interaction
RT with USP7.";
RL Nat. Cell Biol. 13:102-108(2011).
RN [24]
RP FUNCTION, INTERACTION WITH DNMT1 AND UHRF1, AND MUTAGENESIS OF
RP CYS-223.
RX PubMed=21745816; DOI=10.1093/nar/gkr528;
RA Felle M., Joppien S., Nemeth A., Diermeier S., Thalhammer V.,
RA Dobner T., Kremmer E., Kappler R., Langst G.;
RT "The USP7/Dnmt1 complex stimulates the DNA methylation activity of
RT Dnmt1 and regulates the stability of UHRF1.";
RL Nucleic Acids Res. 39:8355-8365(2011).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-18, AND MASS
RP SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [26]
RP FUNCTION, INTERACTION WITH UHRF1, AND MUTAGENESIS OF CYS-223.
RX PubMed=22411829; DOI=10.1073/pnas.1116349109;
RA Ma H., Chen H., Guo X., Wang Z., Sowa M.E., Zheng L., Hu S., Zeng P.,
RA Guo R., Diao J., Lan F., Harper J.W., Shi Y.G., Xu Y., Shi Y.;
RT "M phase phosphorylation of the epigenetic regulator UHRF1 regulates
RT its physical association with the deubiquitylase USP7 and stability.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:4828-4833(2012).
RN [27]
RP FUNCTION, AND LINKAGE SPECIFICITY.
RX PubMed=22689415; DOI=10.1002/cbic.201200261;
RA Iphofer A., Kummer A., Nimtz M., Ritter A., Arnold T., Frank R.,
RA van den Heuvel J., Kessler B.M., Jansch L., Franke R.;
RT "Profiling ubiquitin linkage specificities of deubiquitinating enzymes
RT with branched ubiquitin isopeptide probes.";
RL ChemBioChem 13:1416-1420(2012).
RN [28]
RP INTERACTION WITH MEX3C.
RX PubMed=22863774; DOI=10.1038/emboj.2012.218;
RA Cano F., Bye H., Duncan L.M., Buchet-Poyau K., Billaud M., Wills M.R.,
RA Lehner P.J.;
RT "The RNA-binding E3 ubiquitin ligase MEX-3C links ubiquitination with
RT MHC-I mRNA degradation.";
RL EMBO J. 31:3596-3606(2012).
RN [29]
RP FUNCTION, AND INTERACTION WITH UVSSA.
RX PubMed=22466611; DOI=10.1038/ng.2230;
RA Schwertman P., Lagarou A., Dekkers D.H., Raams A., van der Hoek A.C.,
RA Laffeber C., Hoeijmakers J.H., Demmers J.A., Fousteri M.,
RA Vermeulen W., Marteijn J.A.;
RT "UV-sensitive syndrome protein UVSSA recruits USP7 to regulate
RT transcription-coupled repair.";
RL Nat. Genet. 44:598-602(2012).
RN [30]
RP FUNCTION, AND INTERACTION WITH UVSSA.
RX PubMed=22466612; DOI=10.1038/ng.2228;
RA Zhang X., Horibata K., Saijo M., Ishigami C., Ukai A., Kanno S.I.,
RA Tahara H., Neilan E.G., Honma M., Nohmi T., Yasui A., Tanaka K.;
RT "Mutations in UVSSA cause UV-sensitive syndrome and destabilize ERCC6
RT in transcription-coupled DNA repair.";
RL Nat. Genet. 44:593-597(2012).
RN [31]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 208-560 IN COMPLEX WITH
RP UBIQUITIN, MUTAGENESIS OF CYS-223; HIS-456 AND HIS-464, AND
RP INTERACTION WITH TP53.
RX PubMed=12507430; DOI=10.1016/S0092-8674(02)01199-6;
RA Hu M., Li P., Li M., Li W., Yao T., Wu J.-W., Gu W., Cohen R.E.,
RA Shi Y.;
RT "Crystal structure of a UBP-family deubiquitinating enzyme in
RT isolation and in complex with ubiquitin aldehyde.";
RL Cell 111:1041-1054(2002).
RN [32]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 54-205 IN COMPLEX WITH EBNA1,
RP AND INTERACTION WITH EBV EBNA1.
RX PubMed=15808506; DOI=10.1016/j.molcel.2005.02.029;
RA Saridakis V., Sheng Y., Sarkari F., Holowaty M.N., Shire K.,
RA Nguyen T., Zhang R.G., Liao J., Lee W., Edwards A.M., Arrowsmith C.H.,
RA Frappier L.;
RT "Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-
RT Barr nuclear antigen 1 implications for EBV-mediated
RT immortalization.";
RL Mol. Cell 18:25-36(2005).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 43-560 IN COMPLEX WITH TP53
RP AND MDM2, AND INTERACTION WITH TP53 AND MDM2.
RX PubMed=16402859; DOI=10.1371/journal.pbio.0040027;
RA Hu M., Gu L., Li M., Jeffrey P.D., Gu W., Shi Y.;
RT "Structural basis of competitive recognition of p53 and MDM2 by
RT HAUSP/USP7: implications for the regulation of the p53-MDM2 pathway.";
RL PLoS Biol. 4:228-239(2006).
RN [34]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 54-205 IN COMPLEX WITH TP53
RP AND MDM2, INTERACTION WITH TP53 AND MDM2, AND MUTAGENESIS OF ASP-164
RP AND TRP-165.
RX PubMed=16474402; DOI=10.1038/nsmb1067;
RA Sheng Y., Saridakis V., Sarkari F., Duan S., Wu T., Arrowsmith C.H.,
RA Frappier L.;
RT "Molecular recognition of p53 and MDM2 by USP7/HAUSP.";
RL Nat. Struct. Mol. Biol. 13:285-291(2006).
CC -!- FUNCTION: Hydrolase that deubiquitinates target proteins such as
CC FOXO4, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN and DAXX.
CC Together with DAXX, prevents MDM2 self-ubiquitination and enhances
CC the E3 ligase activity of MDM2 towards p53/TP53, thereby promoting
CC p53/TP53 ubiquitination and proteasomal degradation.
CC Deubiquitinates p53/TP53 and MDM2 and strongly stabilizes p53/TP53
CC even in the presence of excess MDM2, and also induces p53/TP53-
CC dependent cell growth repression and apoptosis. Deubiquitination
CC of FOXO4 in presence of hydrogen peroxide is not dependent on
CC p53/TP53 and inhibits FOXO4-induced transcriptional activity. In
CC association with DAXX, is involved in the deubiquitination and
CC translocation of PTEN from the nucleus to the cytoplasm, both
CC processes that are counteracted by PML. Involved in cell
CC proliferation during early embryonic development. Involved in
CC transcription-coupled nucleotide excision repair (TC-NER) in
CC response to UV damage: recruited to DNA damage sites following
CC interaction with KIAA1530/UVSSA and promotes deubiquitination of
CC ERCC6, preventing UV-induced degradation of ERCC6. Contributes to
CC the overall stabilization and trans-activation capability of the
CC herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110
CC during HSV-1 infection. Involved in maintenance of DNA methylation
CC via its interaction with UHRF1 and DNMT1: acts by mediating
CC deubiquitination of UHRF1 and DNMT1, preventing their degradation
CC and promoting DNA methylation by DNMT1. Exhibits a preference
CC towards 'Lys-48'-linked Ubiquitin chains.
CC -!- CATALYTIC ACTIVITY: Thiol-dependent hydrolysis of ester,
CC thioester, amide, peptide and isopeptide bonds formed by the C-
CC terminal Gly of ubiquitin (a 76-residue protein attached to
CC proteins as an intracellular targeting signal).
CC -!- ENZYME REGULATION: Inhibited by N-ethyl-maleimide (NEM) and
CC divalent cations. Tolerates high concentrations of NaCl but is
CC inhibited at concentrations of 195 mM and higher.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC pH dependence:
CC Active from pH 7.0 to 9.5;
CC -!- SUBUNIT: Monomer. Homodimer. Part of a complex with DAXX, MDM2,
CC RASSF1 and USP7. Part of a complex with DAXX, MDM2 and USP7.
CC Interacts with MDM2; the interaction is independent of p53/TP53.
CC Interacts with DAXX; the interaction is direct and independent of
CC MDM2 and p53/TP53. Interacts with FOXO4; the interaction is
CC enhanced in presence of hydrogen peroxide and occurs independently
CC of p53/TP53. Interacts with p53/TP53; the interaction is enhanced
CC in response to DNA damage; the interaction is impaired by TSPYL5.
CC Interacts with PTEN; the interaction is direct. Interacts with
CC UBXN6. Interacts with ATXN1 and the strength of interaction is
CC influenced by the length of the poly-Gln region in ATXN1. A weaker
CC interaction seen with mutants having longer poly-Gln regions.
CC Interacts with KIAA1530/UVSSA. Isoform 1 and isoform 2 interact
CC with herpesvirus 1 trans-acting transcriptional protein
CC ICP0/VMW110. Interacts with Epstein-Barr virus EBNA1. EBNA1 shows
CC a 10-fold higher affinity than p53/TP53 and can compete with it
CC for USP7 binding. Binding to ICP0/VMW110 may modulate the
CC substrate specificity or activity of USP7 to stabilize viral
CC proteins. Interacts with MEX3C and antagonizes its ability to
CC degrade mRNA. Interacts with DNMT1 and UHRF1.
CC -!- INTERACTION:
CC P35226:BMI1; NbExp=7; IntAct=EBI-302474, EBI-2341576;
CC Q9HC52:CBX8; NbExp=7; IntAct=EBI-302474, EBI-712912;
CC Q9UER7:DAXX; NbExp=13; IntAct=EBI-302474, EBI-77321;
CC P03211:EBNA1 (xeno); NbExp=4; IntAct=EBI-302474, EBI-996522;
CC P21145:MAL; NbExp=3; IntAct=EBI-302474, EBI-3932027;
CC Q00987:MDM2; NbExp=18; IntAct=EBI-302474, EBI-389668;
CC O15151:MDM4; NbExp=15; IntAct=EBI-302474, EBI-398437;
CC O35618:Mdm4 (xeno); NbExp=4; IntAct=EBI-302474, EBI-2603376;
CC Q5U5Q3:MEX3C; NbExp=3; IntAct=EBI-302474, EBI-2864451;
CC Q99836:MYD88; NbExp=3; IntAct=EBI-302474, EBI-447677;
CC P35227:PCGF2; NbExp=5; IntAct=EBI-302474, EBI-2129767;
CC Q06587:RING1; NbExp=4; IntAct=EBI-302474, EBI-752313;
CC Q99496:RNF2; NbExp=4; IntAct=EBI-302474, EBI-722416;
CC P84022:SMAD3; NbExp=2; IntAct=EBI-302474, EBI-347161;
CC Q99426:TBCB; NbExp=2; IntAct=EBI-302474, EBI-764356;
CC P04637:TP53; NbExp=17; IntAct=EBI-302474, EBI-366083;
CC Q86VY4:TSPYL5; NbExp=4; IntAct=EBI-302474, EBI-3436472;
CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Nucleus, PML body.
CC Note=Present in a minority of ND10 nuclear bodies. Association
CC with ICP0/VMW110 at early times of infection leads to an increased
CC proportion of USP7-containing ND10. Colocalizes with ATXN1 in the
CC nucleus. Colocalized with DAXX in speckled structures. Colocalized
CC with PML and PTEN in promyelocytic leukemia protein (PML) nuclear
CC bodies.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q93009-1; Sequence=Displayed;
CC Name=2; Synonyms=USP7 beta;
CC IsoId=Q93009-2; Sequence=Not described;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Widely expressed. Overexpressed in prostate
CC cancer.
CC -!- DOMAIN: The C-terminus plays a role in its oligomerization (By
CC similarity).
CC -!- PTM: Isoform 1: Phosphorylated. Isoform 1 is phosphorylated at
CC positions Ser-18 and Ser-963. Isoform 2: Not phosphorylated.
CC -!- PTM: Isoform 1: Polyneddylated. Isoform 2: Not Polyneddylated.
CC -!- PTM: Isoform 1 and isoform 2: Not sumoylated.
CC -!- PTM: Isoform 1 and isoform 2: Polyubiquitinated by herpesvirus 1
CC trans-acting transcriptional protein ICP0/VMW110; leading to its
CC subsequent proteasomal degradation. Isoform 1: Ubiquitinated at
CC Lys-869.
CC -!- SIMILARITY: Belongs to the peptidase C19 family.
CC -!- SIMILARITY: Contains 1 MATH domain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org//Genes/USP7ID42773ch16p13.html";
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DR EMBL; Z72499; CAA96580.1; -; mRNA.
DR EMBL; AC022167; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471112; EAW85194.1; -; Genomic_DNA.
DR RefSeq; NP_003461.2; NM_003470.2.
DR UniGene; Hs.386939; -.
DR PDB; 1NB8; X-ray; 2.30 A; A/B=208-560.
DR PDB; 1NBF; X-ray; 2.30 A; A/B/E=208-560.
DR PDB; 1YY6; X-ray; 1.70 A; A=54-205.
DR PDB; 1YZE; X-ray; 2.00 A; A/B/C=54-205.
DR PDB; 2F1W; X-ray; 1.65 A; A=53-206.
DR PDB; 2F1X; X-ray; 2.30 A; A/B=53-200.
DR PDB; 2F1Y; X-ray; 1.70 A; A=53-198.
DR PDB; 2F1Z; X-ray; 3.20 A; A/B=43-560.
DR PDB; 2FOJ; X-ray; 1.60 A; A=54-205.
DR PDB; 2FOO; X-ray; 2.20 A; A=54-205.
DR PDB; 2FOP; X-ray; 2.10 A; A=54-205.
DR PDB; 2KVR; NMR; -; A=537-664.
DR PDB; 2XXN; X-ray; 1.60 A; A=63-205.
DR PDB; 2YLM; X-ray; 2.70 A; A=560-1084.
DR PDB; 3MQR; X-ray; 1.80 A; A=54-205.
DR PDB; 3MQS; X-ray; 2.40 A; C=54-205.
DR PDB; 4JJQ; X-ray; 1.95 A; A=54-205.
DR PDB; 4KG9; X-ray; 1.70 A; A=54-205.
DR PDBsum; 1NB8; -.
DR PDBsum; 1NBF; -.
DR PDBsum; 1YY6; -.
DR PDBsum; 1YZE; -.
DR PDBsum; 2F1W; -.
DR PDBsum; 2F1X; -.
DR PDBsum; 2F1Y; -.
DR PDBsum; 2F1Z; -.
DR PDBsum; 2FOJ; -.
DR PDBsum; 2FOO; -.
DR PDBsum; 2FOP; -.
DR PDBsum; 2KVR; -.
DR PDBsum; 2XXN; -.
DR PDBsum; 2YLM; -.
DR PDBsum; 3MQR; -.
DR PDBsum; 3MQS; -.
DR PDBsum; 4JJQ; -.
DR PDBsum; 4KG9; -.
DR ProteinModelPortal; Q93009; -.
DR SMR; Q93009; 63-554, 560-1083.
DR DIP; DIP-29053N; -.
DR IntAct; Q93009; 104.
DR MINT; MINT-234628; -.
DR STRING; 9606.ENSP00000343535; -.
DR ChEMBL; CHEMBL2157850; -.
DR MEROPS; C19.016; -.
DR PhosphoSite; Q93009; -.
DR DMDM; 212276477; -.
DR PaxDb; Q93009; -.
DR PRIDE; Q93009; -.
DR DNASU; 7874; -.
DR Ensembl; ENST00000344836; ENSP00000343535; ENSG00000187555.
DR GeneID; 7874; -.
DR KEGG; hsa:7874; -.
DR UCSC; uc002czl.2; human.
DR CTD; 7874; -.
DR GeneCards; GC16M008985; -.
DR H-InvDB; HIX0038590; -.
DR HGNC; HGNC:12630; USP7.
DR HPA; CAB008108; -.
DR HPA; HPA015641; -.
DR MIM; 602519; gene.
DR neXtProt; NX_Q93009; -.
DR PharmGKB; PA37255; -.
DR eggNOG; COG5077; -.
DR HOGENOM; HOG000160240; -.
DR HOVERGEN; HBG018029; -.
DR KO; K11838; -.
DR OMA; MCERAGF; -.
DR OrthoDB; EOG75B84G; -.
DR SignaLink; Q93009; -.
DR EvolutionaryTrace; Q93009; -.
DR GeneWiki; USP7; -.
DR GenomeRNAi; 7874; -.
DR NextBio; 30332; -.
DR PRO; PR:Q93009; -.
DR ArrayExpress; Q93009; -.
DR Bgee; Q93009; -.
DR CleanEx; HS_USP7; -.
DR Genevestigator; Q93009; -.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0016605; C:PML body; IEA:UniProtKB-SubCell.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IMP:UniProtKB.
DR GO; GO:0004843; F:deubiquitinase activity; IDA:UniProtKB.
DR GO; GO:0002039; F:p53 binding; IDA:UniProtKB.
DR GO; GO:0004221; F:ubiquitin thiolesterase activity; IDA:UniProtKB.
DR GO; GO:0010216; P:maintenance of DNA methylation; IMP:UniProtKB.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0007275; P:multicellular organismal development; IEA:UniProtKB-KW.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IDA:UniProtKB.
DR GO; GO:0016579; P:protein deubiquitination; IDA:UniProtKB.
DR GO; GO:0006283; P:transcription-coupled nucleotide-excision repair; IMP:UniProtKB.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IEA:InterPro.
DR InterPro; IPR002083; MATH.
DR InterPro; IPR018200; Pept_C19ubi-hydrolase_C_CS.
DR InterPro; IPR001394; Peptidase_C19/C67.
DR InterPro; IPR008974; TRAF-like.
DR InterPro; IPR024729; USP7_ICP0-binding_dom.
DR Pfam; PF00917; MATH; 1.
DR Pfam; PF00443; UCH; 1.
DR Pfam; PF12436; USP7_ICP0_bdg; 1.
DR SMART; SM00061; MATH; 1.
DR SUPFAM; SSF49599; SSF49599; 1.
DR PROSITE; PS50144; MATH; 1.
DR PROSITE; PS00972; UCH_2_1; 1.
DR PROSITE; PS00973; UCH_2_2; 1.
DR PROSITE; PS50235; UCH_2_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Cytoplasm; Developmental protein; Direct protein sequencing;
KW DNA damage; DNA repair; Host-virus interaction; Hydrolase;
KW Isopeptide bond; Nucleus; Phosphoprotein; Protease;
KW Reference proteome; Thiol protease; Ubl conjugation;
KW Ubl conjugation pathway.
FT CHAIN 1 1102 Ubiquitin carboxyl-terminal hydrolase 7.
FT /FTId=PRO_0000080626.
FT DOMAIN 68 195 MATH.
FT REGION 1 208 Interaction with TSPYL5.
FT REGION 53 208 Interaction with p53/TP53, MDM2 and
FT EBNA1.
FT REGION 70 205 Necessary for nuclear localization.
FT REGION 622 801 Interaction with ICP0/VMW110.
FT COMPBIAS 4 10 Poly-Gln.
FT ACT_SITE 223 223 Nucleophile.
FT ACT_SITE 464 464 Proton acceptor (Probable).
FT MOD_RES 18 18 Phosphoserine.
FT MOD_RES 869 869 N6-acetyllysine; alternate.
FT MOD_RES 963 963 Phosphoserine.
FT MOD_RES 1084 1084 N6-acetyllysine.
FT MOD_RES 1096 1096 N6-acetyllysine.
FT CROSSLNK 869 869 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin);
FT alternate.
FT MUTAGEN 164 164 D->A: Decreased binding to p53/TP53 and
FT MDM2.
FT MUTAGEN 165 165 W->A: Loss of binding to p53/TP53 and
FT MDM2.
FT MUTAGEN 223 223 C->A: Complete loss of activity.
FT Localized in the nucleus and does not
FT inhibit FOXO4-dependent transcriptional
FT activity.
FT MUTAGEN 223 223 C->S: No effect on p53/TP53 and PTEN
FT binding but is defective in
FT deubiquitinating p53/TP53 and PTEN.
FT MUTAGEN 456 456 H->A: Complete loss of activity.
FT MUTAGEN 464 464 H->A: Complete loss of activity.
FT CONFLICT 201 201 H -> I (in Ref. 1; AA sequence).
FT CONFLICT 205 205 W -> P (in Ref. 1; AA sequence).
FT CONFLICT 207 207 S -> Q (in Ref. 1; AA sequence).
FT CONFLICT 1045 1045 M -> T (in Ref. 1; CAA96580).
FT CONFLICT 1066 1066 Q -> T (in Ref. 1; AA sequence).
FT STRAND 67 77
FT HELIX 78 80
FT STRAND 90 92
FT STRAND 95 104
FT STRAND 113 122
FT STRAND 131 140
FT HELIX 146 148
FT STRAND 150 159
FT HELIX 160 162
FT STRAND 164 172
FT HELIX 173 176
FT TURN 179 181
FT STRAND 182 185
FT STRAND 188 197
FT STRAND 201 203
FT STRAND 210 212
FT TURN 221 224
FT HELIX 225 233
FT HELIX 236 243
FT TURN 252 254
FT HELIX 256 269
FT HELIX 277 283
FT TURN 288 293
FT HELIX 296 310
FT TURN 311 313
FT TURN 315 318
FT HELIX 319 324
FT STRAND 326 337
FT STRAND 340 348
FT STRAND 350 352
FT HELIX 360 367
FT STRAND 371 373
FT TURN 375 377
FT HELIX 382 384
FT STRAND 389 396
FT STRAND 400 406
FT STRAND 409 412
FT TURN 413 416
FT STRAND 417 420
FT STRAND 429 432
FT HELIX 434 436
FT STRAND 437 439
FT STRAND 447 459
FT STRAND 465 469
FT STRAND 473 475
FT STRAND 478 481
FT STRAND 484 487
FT HELIX 490 493
FT HELIX 495 497
FT TURN 507 510
FT STRAND 511 520
FT TURN 521 523
FT HELIX 524 527
FT HELIX 533 535
FT HELIX 538 552
FT HELIX 561 563
FT STRAND 564 571
FT HELIX 572 575
FT STRAND 580 583
FT TURN 586 588
FT STRAND 592 597
FT HELIX 602 613
FT HELIX 617 619
FT STRAND 620 627
FT STRAND 633 635
FT HELIX 640 643
FT HELIX 648 652
FT STRAND 656 664
FT HELIX 667 670
FT TURN 671 673
FT TURN 681 683
FT STRAND 684 693
FT TURN 694 697
FT STRAND 698 708
FT HELIX 713 715
FT HELIX 717 724
FT STRAND 732 739
FT STRAND 742 745
FT STRAND 749 752
FT HELIX 753 756
FT STRAND 764 770
FT HELIX 773 777
FT STRAND 778 780
FT HELIX 783 792
FT STRAND 793 800
FT STRAND 809 814
FT HELIX 819 830
FT HELIX 834 836
FT STRAND 837 840
FT HELIX 861 864
FT STRAND 870 872
FT STRAND 875 880
FT HELIX 885 889
FT STRAND 894 899
FT STRAND 905 910
FT HELIX 918 926
FT STRAND 939 945
FT STRAND 948 953
FT HELIX 959 961
FT STRAND 969 974
FT HELIX 977 979
FT TURN 984 986
FT STRAND 987 998
FT STRAND 1002 1012
FT HELIX 1017 1028
FT HELIX 1032 1035
FT STRAND 1039 1044
FT STRAND 1047 1050
FT TURN 1053 1055
FT HELIX 1060 1062
FT STRAND 1070 1072
FT STRAND 1076 1080
SQ SEQUENCE 1102 AA; 128302 MW; F1A5A5C421396E45 CRC64;
MNHQQQQQQQ KAGEQQLSEP EDMEMEAGDT DDPPRITQNP VINGNVALSD GHNTAEEDME
DDTSWRSEAT FQFTVERFSR LSESVLSPPC FVRNLPWKIM VMPRFYPDRP HQKSVGFFLQ
CNAESDSTSW SCHAQAVLKI INYRDDEKSF SRRISHLFFH KENDWGFSNF MAWSEVTDPE
KGFIDDDKVT FEVFVQADAP HGVAWDSKKH TGYVGLKNQG ATCYMNSLLQ TLFFTNQLRK
AVYMMPTEGD DSSKSVPLAL QRVFYELQHS DKPVGTKKLT KSFGWETLDS FMQHDVQELC
RVLLDNVENK MKGTCVEGTI PKLFRGKMVS YIQCKEVDYR SDRREDYYDI QLSIKGKKNI
FESFVDYVAV EQLDGDNKYD AGEHGLQEAE KGVKFLTLPP VLHLQLMRFM YDPQTDQNIK
INDRFEFPEQ LPLDEFLQKT DPKDPANYIL HAVLVHSGDN HGGHYVVYLN PKGDGKWCKF
DDDVVSRCTK EEAIEHNYGG HDDDLSVRHC TNAYMLVYIR ESKLSEVLQA VTDHDIPQQL
VERLQEEKRI EAQKRKERQE AHLYMQVQIV AEDQFCGHQG NDMYDEEKVK YTVFKVLKNS
SLAEFVQSLS QTMGFPQDQI RLWPMQARSN GTKRPAMLDN EADGNKTMIE LSDNENPWTI
FLETVDPELA ASGATLPKFD KDHDVMLFLK MYDPKTRSLN YCGHIYTPIS CKIRDLLPVM
CDRAGFIQDT SLILYEEVKP NLTERIQDYD VSLDKALDEL MDGDIIVFQK DDPENDNSEL
PTAKEYFRDL YHRVDVIFCD KTIPNDPGFV VTLSNRMNYF QVAKTVAQRL NTDPMLLQFF
KSQGYRDGPG NPLRHNYEGT LRDLLQFFKP RQPKKLYYQQ LKMKITDFEN RRSFKCIWLN
SQFREEEITL YPDKHGCVRD LLEECKKAVE LGEKASGKLR LLEIVSYKII GVHQEDELLE
CLSPATSRTF RIEEIPLDQV DIDKENEMLV TVAHFHKEVF GTFGIPFLLR IHQGEHFREV
MKRIQSLLDI QEKEFEKFKF AIVMMGRHQY INEDEYEVNL KDFEPQPGNM SHPRPWLGLD
HFNKAPKRSR YTYLEKAIKI HN
//
MIM
602519
*RECORD*
*FIELD* NO
602519
*FIELD* TI
*602519 UBIQUITIN-SPECIFIC PROTEASE 7; USP7
;;UBIQUITIN-SPECIFIC PROTEASE, HERPESVIRUS-ASSOCIATED;;
read moreHERPESVIRUS-ASSOCIATED UBIQUITIN-SPECIFIC PROTEASE; HAUSP;;
VMW110-ASSOCIATED PROTEIN, 135-KD
*FIELD* TX
CLONING
Herpes simplex virus type 1 (HSV-1) immediate-early protein Vmw110 is a
nonspecific activator of gene expression and is required for efficient
initiation of the viral lytic cycle. Vmw110 has been shown to bind to
PML (102578)-containing nuclear bodies (ND10) and a 135-kD cellular
protein. By screening a HeLa cell cDNA library with oligonucleotides
based on the amino acid sequence of the purified 135-kD protein, Everett
et al. (1997) cloned a cDNA encoding Vmw110-associated 135-kD protein,
called herpesvirus-associated ubiquitin-specific protease (HAUSP) by
them. The 1,102-amino acid HAUSP protein contains the 2 highly conserved
active site domains of ubiquitin-specific proteases (USPs), a
polyglutamine tract near the N terminus, and several regions predicted
to form alpha helices. The authors showed that HAUSP can cleave model
substrates of USPs. By immunofluorescence, they found that HAUSP is a
predominantly nuclear protein that is present in a minority of ND10.
Expression of Vmw110 early in virus infection increases the proportion
of ND10 that contain HAUSP. Everett et al. (1997) stated that these
results implicate a novel ubiquitin-dependent pathway in both the
function of ND10 and the control of viral gene expression. Northern blot
analysis of HeLa cell poly(A)+ RNA detected 2 low-level transcripts, 1
approximately 4.5 kb and the other slightly larger and of lower
abundance. The NCBI dbEST database contains expressed sequence tags that
match the HAUSP sequence and are derived from brain, liver, placenta,
lung, and melanocyte cDNA libraries, suggesting that HAUSP is expressed
in a wide variety of cell types.
Zapata et al. (2001) identified an N-terminal TRAF (see 601711)-like
domain in USP7. USP7 localized predominantly to the nucleus in
transfected COS-7 cells, and localization required the TRAF-like domain.
In USP7, Holowaty et al. (2003) identified an N-terminal p53
(191170)-binding domain, a catalytic domain, and 2 C-terminal domains.
The p53-binding domain is identical to the TRAF-like domain described by
Zapata et al. (2001).
GENE FUNCTION
By mass spectrometry of affinity-purified p53-associated factors, Li et
al. (2002) identified HAUSP as a novel p53-interacting protein. HAUSP
strongly stabilizes p53 even in the presence of excess MDM2 (164785),
and also induces p53-dependent cell growth repression and apoptosis.
HAUSP has an intrinsic enzymatic activity that specifically
deubiquitinates p53 both in vivo and in vitro. Expression of a
catalytically inactive point mutation of HAUSP in cells increased the
levels of p53 ubiquitination and also destabilized p53. Li et al. (2002)
concluded that their findings revealed an important mechanism by which
p53 can be stabilized by direct deubiquitination and also implied that
HAUSP may function as a tumor suppressor in vivo through the
stabilization of p53.
Zapata et al. (2001) found that the TRAF-like domain of USP7 could
interact in vitro with all TRAF proteins tested. The TRAF-like domain
also suppressed NFKB (see 164011) induction by TRAF2 (601895), TRAF6
(602355), and some TRAF-binding TNF receptors (see 191190).
Holowaty et al. (2003) determined that in vitro translated USP7 could
hydrolyze a linear ubiquitin fusion protein. Biochemical
characterization indicated that deubiquitination by USP7 was resistant
to high salt concentrations and high pH, but it was inactivated by a
thiol-blocking reagent. USP7 also removed ubiquitin from a high
molecular mass polyubiquitinated Epstein-Barr virus protein, EBNA1. By
mutation analysis, proteolysis protection assays, and several protein
binding assays, Holowaty et al. (2003) determined that the N-terminal
p53-binding domain of USP7 interacted with EBNA1. The binding affinity
between USP7 and EBNA1 was 10-fold higher than that between p53 and
USP7. Holowaty et al. (2003) also determined that a C-terminal domain of
USP7 interacted with the HSV-1 protein ICP0.
The p53 tumor suppressor protein has a major role in protecting the
integrity of the genome, and a balance between the ubiquitin ligase
activity of proteins such as HDM2 (164785) and ubiquitin protease
activity of USP7 determines the half-life of p53. Meulmeester et al.
(2005) demonstrated that USP7 also indirectly affected p53 stability by
deubiquitinating HDMX (602704), a regulator of HDM2. In addition, the
deubiquitination activity of USP7 toward both HDMX and HDM2 was impaired
following DNA damage, although the general activity of USP7 was not
affected.
Song et al. (2008) found that PTEN (601728) was aberrantly localized in
acute promyelocytic leukemia (APL; 612376) in which PML function was
disrupted by the PML-RARA (180240) fusion oncoprotein. Treatment with
drugs that triggered PML-RARA degradation restored nuclear PTEN. PML
opposed the activity of HAUSP towards PTEN through a mechanism involving
DAXX (603186). Confocal microscopy and immunohistochemistry demonstrated
that HAUSP was overexpressed in prostate cancer and that levels of HAUSP
directly correlated with tumor aggressiveness and with PTEN nuclear
exclusion. Song et al. (2008) concluded that a PML-HAUSP network
controls PTEN deubiquitinylation and subcellular localization, which is
perturbed in human cancers.
Independently, Zhang et al. (2012) and Schwertman et al. (2012) showed
that UVSSA (614632) stabilized the transcription-coupled nucleotide
excision repair (NER) organizing protein ERCC6 (609413) by delivering
USP7 to the NER complex. They concluded that UVSSA-USP7-mediated
stabilization of ERCC6 is a critical regulatory mechanism of
transcription-coupled NER, which removes transcription-blocking DNA
damage.
BIOCHEMICAL FEATURES
Hu et al. (2002) reported the crystal structures of the 40-kD catalytic
core domain of HAUSP in isolation and in complex with ubiquitin
aldehyde. These studies revealed that ubiquitin-specific processing
protease (UBP) deubiquitinating enzymes such as HAUSP exhibit a
conserved 3-domain architecture, comprising 'fingers,' 'palm,' and
'thumb.' The leaving ubiquitin moiety is specifically coordinated by the
fingers, with its C terminus placed in the active site between the palm
and the thumb. Binding by ubiquitin aldehyde induces a drastic
conformational change in the active site that realigns the catalytic
triad residues for catalysis.
MAPPING
Based on 197 bp of sequence similarity between the HAUSP gene and a
genomic clone (GenBank GENBANK Z94768), Kashuba et al. (1997)
tentatively mapped the HAUSP gene to 3p21. By fluorescence in situ
hybridization, Robinson et al. (1998) mapped the HAUSP gene to 16p13.3.
*FIELD* RF
1. Everett, R. D.; Meredith, M.; Orr, A.; Cross, A.; Kathoria, M.;
Parkinson, J.: A novel ubiquitin-specific protease is dynamically
associated with the PML nuclear domain and binds to a herpesvirus
regulatory protein. EMBO J. 16: 1519-1530, 1997. Note: Corrected
republication of EMBO J.:16: 566-577, 1997.
2. Holowaty, M. N.; Sheng, Y.; Nguyen, T.; Arrowsmith, C.; Frappier,
L.: Protein interaction domains of the ubiquitin-specific protease,
USP7/HAUSP. J. Biol. Chem. 278: 47753-47761, 2003.
3. Hu, M.; Li, P.; Li, M.; Li, W.; Yao, T.; Wu, J.-W.; Gu, W.; Cohen,
R. E.; Shi, Y.: Crystal structure of a UBP-family deubiquitinating
enzyme in isolation and in complex with ubiquitin aldehyde. Cell 111:
1041-1054, 2002.
4. Kashuba, V. I.; Gizatullin, R. Z.; Protopopov, A. I.; Allikmets,
R.; Korolev, S.; Li, J.; Boldog, F.; Tory, K.; Zabarovska, V.; Marcsek,
Z.; Sumegi, J.; Klein, G.; Zabarovsky, E. R.; Kisselev, L.: NotI
linking/jumping clones of human chromosome 3: mapping of the TFRC,
RAB7 and HAUSP genes to regions rearranged in leukemia and deleted
in solid tumors. FEBS Lett. 419: 181-185, 1997.
5. Li, M.; Chen, D.; Shiloh, A.; Luo, J.; Nikolaev, A. Y.; Qin, J.;
Gu, W.: Deubiquitination of p53 by HAUSP is an important pathway
for p53 stabilization. Nature 416: 648-653, 2002.
6. Meulmeester, E.; Maurice, M. M.; Boutell, C.; Teunisse, A. F. A.
S.; Ovaa, H.; Abraham, T. E.; Dirks, R. W.; Jochemsen, A. G.: Loss
of HAUSP-mediated deubiquitination contributes to DNA damage-induced
destabilization of Hdmx and Hdm2. Molec. Cell 18: 565-576, 2005.
Note: Erratum: Molec. Cell 19: 143-144, 2005.
7. Robinson, P. A.; Lomonte, P.; Leek, J. P.; Markham, A. F.; Everett,
R. D.: Assignment of herpesvirus-associated ubiquitin-specific protease
gene HAUSP to human chromosome band 16p13.3 by in situ hybridization. Cytogenet.
Cell Genet. 83: 100 only, 1998.
8. Schwertman, P.; Lagarou, A.; Dekkers, D. H. W.; Raams, A.; van
der Hoek, A. C.; Laffeber, C.; Hoeijmakers, J. H. J.; Demmers, J.
A. A.; Fousteri, M.; Vermeulen, W.; Marteijn, J. A.: UV-sensitive
syndrome protein UVSSA recruits USP7 to regulate transcription-coupled
repair. Nature Genet. 44: 598-602, 2012.
9. Song, M. S.; Salmena, L.; Carracedo, A.; Egia, A.; Lo-Coco, F.;
Teruya-Feldstein, J.; Pandolfi, P. P.: The deubiquitinylation and
localization of PTEN are regulated by a HAUSP-PML network. Nature 455:
813-817, 2008.
10. Zapata, J. M.; Pawlowski, K.; Haas, E.; Ware, C. F.; Godzik, A.;
Reed, J. C.: A diverse family of proteins containing tumor necrosis
factor receptor-associated factor domains. J. Biol. Chem. 276: 24242-24252,
2001.
11. Zhang, X.; Horibata, K.; Saijo, M.; Ishigami, C.; Ukai, A.; Kanno,
S.; Tahara, H.; Neilan, E. G.; Honma, M.; Nohmi, T.; Yasui, A.; Tanaka,
K.: Mutations in UVSSA cause UV-sensitive syndrome and destabilize
ERCC6 in transcription-coupled DNA repair. Nature Genet. 593-597,
2012.
*FIELD* CN
Patricia A. Hartz - updated: 05/10/2012
Paul J. Converse - updated: 11/18/2008
Patricia A. Hartz - updated: 6/13/2005
Stylianos E. Antonarakis - updated: 1/15/2003
Ada Hamosh - updated: 3/29/2002
Patti M. Sherman - updated: 11/18/1998
*FIELD* CD
Patti M. Sherman: 4/14/1998
*FIELD* ED
mgross: 05/10/2012
mgross: 11/19/2008
terry: 11/18/2008
wwang: 8/8/2005
wwang: 7/7/2005
wwang: 6/28/2005
terry: 6/13/2005
mgross: 1/15/2003
alopez: 4/30/2002
cwells: 4/3/2002
terry: 3/29/2002
psherman: 2/25/1999
alopez: 2/3/1999
carol: 11/18/1998
psherman: 10/19/1998
psherman: 10/13/1998
alopez: 6/23/1998
carol: 5/6/1998
joanna: 5/6/1998
dholmes: 4/14/1998
*RECORD*
*FIELD* NO
602519
*FIELD* TI
*602519 UBIQUITIN-SPECIFIC PROTEASE 7; USP7
;;UBIQUITIN-SPECIFIC PROTEASE, HERPESVIRUS-ASSOCIATED;;
read moreHERPESVIRUS-ASSOCIATED UBIQUITIN-SPECIFIC PROTEASE; HAUSP;;
VMW110-ASSOCIATED PROTEIN, 135-KD
*FIELD* TX
CLONING
Herpes simplex virus type 1 (HSV-1) immediate-early protein Vmw110 is a
nonspecific activator of gene expression and is required for efficient
initiation of the viral lytic cycle. Vmw110 has been shown to bind to
PML (102578)-containing nuclear bodies (ND10) and a 135-kD cellular
protein. By screening a HeLa cell cDNA library with oligonucleotides
based on the amino acid sequence of the purified 135-kD protein, Everett
et al. (1997) cloned a cDNA encoding Vmw110-associated 135-kD protein,
called herpesvirus-associated ubiquitin-specific protease (HAUSP) by
them. The 1,102-amino acid HAUSP protein contains the 2 highly conserved
active site domains of ubiquitin-specific proteases (USPs), a
polyglutamine tract near the N terminus, and several regions predicted
to form alpha helices. The authors showed that HAUSP can cleave model
substrates of USPs. By immunofluorescence, they found that HAUSP is a
predominantly nuclear protein that is present in a minority of ND10.
Expression of Vmw110 early in virus infection increases the proportion
of ND10 that contain HAUSP. Everett et al. (1997) stated that these
results implicate a novel ubiquitin-dependent pathway in both the
function of ND10 and the control of viral gene expression. Northern blot
analysis of HeLa cell poly(A)+ RNA detected 2 low-level transcripts, 1
approximately 4.5 kb and the other slightly larger and of lower
abundance. The NCBI dbEST database contains expressed sequence tags that
match the HAUSP sequence and are derived from brain, liver, placenta,
lung, and melanocyte cDNA libraries, suggesting that HAUSP is expressed
in a wide variety of cell types.
Zapata et al. (2001) identified an N-terminal TRAF (see 601711)-like
domain in USP7. USP7 localized predominantly to the nucleus in
transfected COS-7 cells, and localization required the TRAF-like domain.
In USP7, Holowaty et al. (2003) identified an N-terminal p53
(191170)-binding domain, a catalytic domain, and 2 C-terminal domains.
The p53-binding domain is identical to the TRAF-like domain described by
Zapata et al. (2001).
GENE FUNCTION
By mass spectrometry of affinity-purified p53-associated factors, Li et
al. (2002) identified HAUSP as a novel p53-interacting protein. HAUSP
strongly stabilizes p53 even in the presence of excess MDM2 (164785),
and also induces p53-dependent cell growth repression and apoptosis.
HAUSP has an intrinsic enzymatic activity that specifically
deubiquitinates p53 both in vivo and in vitro. Expression of a
catalytically inactive point mutation of HAUSP in cells increased the
levels of p53 ubiquitination and also destabilized p53. Li et al. (2002)
concluded that their findings revealed an important mechanism by which
p53 can be stabilized by direct deubiquitination and also implied that
HAUSP may function as a tumor suppressor in vivo through the
stabilization of p53.
Zapata et al. (2001) found that the TRAF-like domain of USP7 could
interact in vitro with all TRAF proteins tested. The TRAF-like domain
also suppressed NFKB (see 164011) induction by TRAF2 (601895), TRAF6
(602355), and some TRAF-binding TNF receptors (see 191190).
Holowaty et al. (2003) determined that in vitro translated USP7 could
hydrolyze a linear ubiquitin fusion protein. Biochemical
characterization indicated that deubiquitination by USP7 was resistant
to high salt concentrations and high pH, but it was inactivated by a
thiol-blocking reagent. USP7 also removed ubiquitin from a high
molecular mass polyubiquitinated Epstein-Barr virus protein, EBNA1. By
mutation analysis, proteolysis protection assays, and several protein
binding assays, Holowaty et al. (2003) determined that the N-terminal
p53-binding domain of USP7 interacted with EBNA1. The binding affinity
between USP7 and EBNA1 was 10-fold higher than that between p53 and
USP7. Holowaty et al. (2003) also determined that a C-terminal domain of
USP7 interacted with the HSV-1 protein ICP0.
The p53 tumor suppressor protein has a major role in protecting the
integrity of the genome, and a balance between the ubiquitin ligase
activity of proteins such as HDM2 (164785) and ubiquitin protease
activity of USP7 determines the half-life of p53. Meulmeester et al.
(2005) demonstrated that USP7 also indirectly affected p53 stability by
deubiquitinating HDMX (602704), a regulator of HDM2. In addition, the
deubiquitination activity of USP7 toward both HDMX and HDM2 was impaired
following DNA damage, although the general activity of USP7 was not
affected.
Song et al. (2008) found that PTEN (601728) was aberrantly localized in
acute promyelocytic leukemia (APL; 612376) in which PML function was
disrupted by the PML-RARA (180240) fusion oncoprotein. Treatment with
drugs that triggered PML-RARA degradation restored nuclear PTEN. PML
opposed the activity of HAUSP towards PTEN through a mechanism involving
DAXX (603186). Confocal microscopy and immunohistochemistry demonstrated
that HAUSP was overexpressed in prostate cancer and that levels of HAUSP
directly correlated with tumor aggressiveness and with PTEN nuclear
exclusion. Song et al. (2008) concluded that a PML-HAUSP network
controls PTEN deubiquitinylation and subcellular localization, which is
perturbed in human cancers.
Independently, Zhang et al. (2012) and Schwertman et al. (2012) showed
that UVSSA (614632) stabilized the transcription-coupled nucleotide
excision repair (NER) organizing protein ERCC6 (609413) by delivering
USP7 to the NER complex. They concluded that UVSSA-USP7-mediated
stabilization of ERCC6 is a critical regulatory mechanism of
transcription-coupled NER, which removes transcription-blocking DNA
damage.
BIOCHEMICAL FEATURES
Hu et al. (2002) reported the crystal structures of the 40-kD catalytic
core domain of HAUSP in isolation and in complex with ubiquitin
aldehyde. These studies revealed that ubiquitin-specific processing
protease (UBP) deubiquitinating enzymes such as HAUSP exhibit a
conserved 3-domain architecture, comprising 'fingers,' 'palm,' and
'thumb.' The leaving ubiquitin moiety is specifically coordinated by the
fingers, with its C terminus placed in the active site between the palm
and the thumb. Binding by ubiquitin aldehyde induces a drastic
conformational change in the active site that realigns the catalytic
triad residues for catalysis.
MAPPING
Based on 197 bp of sequence similarity between the HAUSP gene and a
genomic clone (GenBank GENBANK Z94768), Kashuba et al. (1997)
tentatively mapped the HAUSP gene to 3p21. By fluorescence in situ
hybridization, Robinson et al. (1998) mapped the HAUSP gene to 16p13.3.
*FIELD* RF
1. Everett, R. D.; Meredith, M.; Orr, A.; Cross, A.; Kathoria, M.;
Parkinson, J.: A novel ubiquitin-specific protease is dynamically
associated with the PML nuclear domain and binds to a herpesvirus
regulatory protein. EMBO J. 16: 1519-1530, 1997. Note: Corrected
republication of EMBO J.:16: 566-577, 1997.
2. Holowaty, M. N.; Sheng, Y.; Nguyen, T.; Arrowsmith, C.; Frappier,
L.: Protein interaction domains of the ubiquitin-specific protease,
USP7/HAUSP. J. Biol. Chem. 278: 47753-47761, 2003.
3. Hu, M.; Li, P.; Li, M.; Li, W.; Yao, T.; Wu, J.-W.; Gu, W.; Cohen,
R. E.; Shi, Y.: Crystal structure of a UBP-family deubiquitinating
enzyme in isolation and in complex with ubiquitin aldehyde. Cell 111:
1041-1054, 2002.
4. Kashuba, V. I.; Gizatullin, R. Z.; Protopopov, A. I.; Allikmets,
R.; Korolev, S.; Li, J.; Boldog, F.; Tory, K.; Zabarovska, V.; Marcsek,
Z.; Sumegi, J.; Klein, G.; Zabarovsky, E. R.; Kisselev, L.: NotI
linking/jumping clones of human chromosome 3: mapping of the TFRC,
RAB7 and HAUSP genes to regions rearranged in leukemia and deleted
in solid tumors. FEBS Lett. 419: 181-185, 1997.
5. Li, M.; Chen, D.; Shiloh, A.; Luo, J.; Nikolaev, A. Y.; Qin, J.;
Gu, W.: Deubiquitination of p53 by HAUSP is an important pathway
for p53 stabilization. Nature 416: 648-653, 2002.
6. Meulmeester, E.; Maurice, M. M.; Boutell, C.; Teunisse, A. F. A.
S.; Ovaa, H.; Abraham, T. E.; Dirks, R. W.; Jochemsen, A. G.: Loss
of HAUSP-mediated deubiquitination contributes to DNA damage-induced
destabilization of Hdmx and Hdm2. Molec. Cell 18: 565-576, 2005.
Note: Erratum: Molec. Cell 19: 143-144, 2005.
7. Robinson, P. A.; Lomonte, P.; Leek, J. P.; Markham, A. F.; Everett,
R. D.: Assignment of herpesvirus-associated ubiquitin-specific protease
gene HAUSP to human chromosome band 16p13.3 by in situ hybridization. Cytogenet.
Cell Genet. 83: 100 only, 1998.
8. Schwertman, P.; Lagarou, A.; Dekkers, D. H. W.; Raams, A.; van
der Hoek, A. C.; Laffeber, C.; Hoeijmakers, J. H. J.; Demmers, J.
A. A.; Fousteri, M.; Vermeulen, W.; Marteijn, J. A.: UV-sensitive
syndrome protein UVSSA recruits USP7 to regulate transcription-coupled
repair. Nature Genet. 44: 598-602, 2012.
9. Song, M. S.; Salmena, L.; Carracedo, A.; Egia, A.; Lo-Coco, F.;
Teruya-Feldstein, J.; Pandolfi, P. P.: The deubiquitinylation and
localization of PTEN are regulated by a HAUSP-PML network. Nature 455:
813-817, 2008.
10. Zapata, J. M.; Pawlowski, K.; Haas, E.; Ware, C. F.; Godzik, A.;
Reed, J. C.: A diverse family of proteins containing tumor necrosis
factor receptor-associated factor domains. J. Biol. Chem. 276: 24242-24252,
2001.
11. Zhang, X.; Horibata, K.; Saijo, M.; Ishigami, C.; Ukai, A.; Kanno,
S.; Tahara, H.; Neilan, E. G.; Honma, M.; Nohmi, T.; Yasui, A.; Tanaka,
K.: Mutations in UVSSA cause UV-sensitive syndrome and destabilize
ERCC6 in transcription-coupled DNA repair. Nature Genet. 593-597,
2012.
*FIELD* CN
Patricia A. Hartz - updated: 05/10/2012
Paul J. Converse - updated: 11/18/2008
Patricia A. Hartz - updated: 6/13/2005
Stylianos E. Antonarakis - updated: 1/15/2003
Ada Hamosh - updated: 3/29/2002
Patti M. Sherman - updated: 11/18/1998
*FIELD* CD
Patti M. Sherman: 4/14/1998
*FIELD* ED
mgross: 05/10/2012
mgross: 11/19/2008
terry: 11/18/2008
wwang: 8/8/2005
wwang: 7/7/2005
wwang: 6/28/2005
terry: 6/13/2005
mgross: 1/15/2003
alopez: 4/30/2002
cwells: 4/3/2002
terry: 3/29/2002
psherman: 2/25/1999
alopez: 2/3/1999
carol: 11/18/1998
psherman: 10/19/1998
psherman: 10/13/1998
alopez: 6/23/1998
carol: 5/6/1998
joanna: 5/6/1998
dholmes: 4/14/1998