ID   UBP7_RAT                Reviewed;        1103 AA.
AC   Q4VSI4;
DT   12-DEC-2006, integrated into UniProtKB/Swiss-Prot.
DT   05-JUL-2005, sequence version 1.
DT   27-MAR-2024, entry version 131.
DE   RecName: Full=Ubiquitin carboxyl-terminal hydrolase 7;
DE            EC=3.4.19.12 {ECO:0000269|PubMed:16111684, ECO:0000269|PubMed:16328052};
DE   AltName: Full=Deubiquitinating enzyme 7;
DE   AltName: Full=Herpesvirus-associated ubiquitin-specific protease;
DE            Short=rHAUSP;
DE   AltName: Full=Ubiquitin thioesterase 7;
DE   AltName: Full=Ubiquitin-specific-processing protease 7;
GN   Name=Usp7; Synonyms=Hausp;
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, TISSUE
RP   SPECIFICITY, MUTAGENESIS OF CYS-224, POLYUBIQUITINATION, AND
RP   POLYNEDDYLATION.
RC   TISSUE=Testis;
RX   PubMed=16111684; DOI=10.1016/j.febslet.2005.07.048;
RA   Lee H.-J., Kim M.-S., Kim Y.-K., Oh Y.-K., Baek K.-H.;
RT   "HAUSP, a deubiquitinating enzyme for p53, is polyubiquitinated,
RT   polyneddylated, and dimerized.";
RL   FEBS Lett. 579:4867-4872(2005).
RN   [2]
RP   FUNCTION, CATALYTIC ACTIVITY, UBIQUITINATION, AND MUTAGENESIS OF CYS-224.
RC   TISSUE=Testis;
RX   PubMed=16328052;
RA   Baek K.H., Lee H.J., Kim M.S., Kim Y.S., Seong M., Lee E.J., Lee M.Y.;
RT   "Molecular cloning of rHAUSP encoding a deubiquitinating enzyme in rat
RT   testis.";
RL   Oncol. Rep. 15:173-177(2006).
RN   [3]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-19, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=22673903; DOI=10.1038/ncomms1871;
RA   Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA   Olsen J.V.;
RT   "Quantitative maps of protein phosphorylation sites across 14 different rat
RT   organs and tissues.";
RL   Nat. Commun. 3:876-876(2012).
CC   -!- FUNCTION: Hydrolase that deubiquitinates target proteins such as FOXO4,
CC       DEPTOR, KAT5, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN, KMT2E/MLL5 and
CC       DAXX (PubMed:16111684, PubMed:16328052). Together with DAXX, prevents
CC       MDM2 self-ubiquitination and enhances the E3 ligase activity of MDM2
CC       towards p53/TP53, thereby promoting p53/TP53 ubiquitination and
CC       proteasomal degradation (By similarity). Deubiquitinates p53/TP53,
CC       preventing degradation of p53/TP53, and enhances p53/TP53-dependent
CC       transcription regulation, cell growth repression and apoptosis (By
CC       similarity). Deubiquitinates p53/TP53 and MDM2 and strongly stabilizes
CC       p53/TP53 even in the presence of excess MDM2, and also induces
CC       p53/TP53-dependent cell growth repression and apoptosis (By
CC       similarity). Deubiquitination of FOXO4 in presence of hydrogen peroxide
CC       is not dependent on p53/TP53 and inhibits FOXO4-induced transcriptional
CC       activity. In association with DAXX, is involved in the deubiquitination
CC       and translocation of PTEN from the nucleus to the cytoplasm, both
CC       processes that are counteracted by PML (By similarity). Deubiquitinates
CC       KMT2E preventing KMT2E proteasomal-mediated degradation (By
CC       similarity). Involved in cell proliferation during early embryonic
CC       development (By similarity). Involved in transcription-coupled
CC       nucleotide excision repair (TC-NER) in response to UV damage: recruited
CC       to DNA damage sites following interaction with KIAA1530/UVSSA and
CC       promotes deubiquitination of ERCC6, preventing UV-induced degradation
CC       of ERCC6 (By similarity). 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 and
CC       promoting DNA methylation by DNMT1 (By similarity). Deubiquitinates
CC       alkylation repair enzyme ALKBH3. OTUD4 recruits USP7 and USP9X to
CC       stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions
CC       (By similarity). Acts as a chromatin regulator via its association with
CC       the Polycomb group (PcG) multiprotein PRC1-like complex; may act by
CC       deubiquitinating components of the PRC1-like complex (By similarity).
CC       Able to mediate deubiquitination of histone H2B; it is however unsure
CC       whether this activity takes place in vivo (By similarity). Exhibits a
CC       preference towards 'Lys-48'-linked ubiquitin chains. Increases
CC       regulatory T-cells (Treg) suppressive capacity by deubiquitinating and
CC       stabilizing transcription factor FOXP3 which is crucial for Treg cell
CC       function (By similarity). Plays a role in the maintenance of the
CC       circadian clock periodicity via deubiquitination and stabilization of
CC       the CRY1 and CRY2 proteins (By similarity). Deubiquitinates REST,
CC       thereby stabilizing REST and promoting the maintenance of neural
CC       progenitor cells (By similarity). Deubiquitinates SIRT7, inhibiting
CC       SIRT7 histone deacetylase activity and regulating gluconeogenesis (By
CC       similarity). Involved in the regulation of WASH-dependent actin
CC       polymerization at the surface of endosomes and the regulation of
CC       endosomal protein recycling (By similarity). It maintains optimal WASH
CC       complex activity and precise F-actin levels via deubiquitination of
CC       TRIM27 and WASHC1 (By similarity). Mediates the deubiquitination of
CC       phosphorylated DEPTOR, promoting its stability and leading to decreased
CC       mTORC1 signaling (By similarity). {ECO:0000250|UniProtKB:Q93009,
CC       ECO:0000269|PubMed:16111684, ECO:0000269|PubMed:16328052}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide
CC         and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-
CC         residue protein attached to proteins as an intracellular targeting
CC         signal).; EC=3.4.19.12; Evidence={ECO:0000269|PubMed:16111684,
CC         ECO:0000269|PubMed:16328052};
CC   -!- SUBUNIT: Monomer. Homodimer (PubMed:16111684). Part of a complex with
CC       DAXX, MDM2, RASSF1 and USP7. Part of a complex with DAXX, MDM2 and
CC       USP7. Interacts with MDM2; the interaction is independent of p53/TP53.
CC       Interacts with DAXX; the interaction is direct and independent of MDM2
CC       and p53/TP53. Component of a complex composed of KMT2E, OGT and USP7;
CC       the complex stabilizes KMT2E, preventing KMT2E ubiquitination and
CC       proteasomal-mediated degradation (By similarity). Interacts (via MATH
CC       domain) with KMT2E (By similarity). Interacts with OGT (By similarity).
CC       Interacts with FOXO4; the interaction is enhanced in presence of
CC       hydrogen peroxide and occurs independently of p53/TP53. Interacts with
CC       p53/TP53; the interaction is enhanced in response to DNA damage; the
CC       interaction is impaired by TSPYL5. Interacts with PTEN; the interaction
CC       is direct. 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. Interacts
CC       with KIAA1530/UVSSA. Interacts with MEX3C and antagonizes its ability
CC       to degrade mRNA. Interacts with DNMT1 and UHRF1. Interacts with FOXP3.
CC       Interacts (via MATH domain) with RNF220 (By similarity). Associated
CC       component of the Polycomb group (PcG) multiprotein PRC1-like complex
CC       (By similarity). Interacts with EPOP (By similarity). Interacts with
CC       OTUD4 and USP9X; the interaction is direct (By similarity). Interacts
CC       with CRY2 (By similarity). Interacts with REST (By similarity).
CC       Interacts with ERCC6 (By similarity). Part of a complex consisting of
CC       USP7, MAGEL2 and TRIM27; directly interacts with MAGEL2; directly
CC       interacts with TRIM27 (By similarity). {ECO:0000250|UniProtKB:Q6A4J8,
CC       ECO:0000250|UniProtKB:Q93009, ECO:0000269|PubMed:16111684}.
CC   -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:Q93009}. Cytoplasm
CC       {ECO:0000250|UniProtKB:Q93009}. Nucleus, PML body
CC       {ECO:0000250|UniProtKB:Q93009}. Chromosome
CC       {ECO:0000250|UniProtKB:Q93009}. Note=Present in a minority of ND10
CC       nuclear bodies. Association with ICP0/VMW110 at early times of
CC       infection leads to an increased proportion of USP7-containing ND10.
CC       Colocalizes with ATXN1 in the nucleus. Colocalized with DAXX in
CC       speckled structures. Colocalized with PML and PTEN in promyelocytic
CC       leukemia protein (PML) nuclear bodies. {ECO:0000250|UniProtKB:Q93009}.
CC   -!- TISSUE SPECIFICITY: Strongly expressed in the testis, spleen and brain.
CC       Weakly expressed in the stomach, small intestine, skeletal muscle and
CC       uterus. {ECO:0000269|PubMed:16111684}.
CC   -!- DOMAIN: The C-terminus plays a role in its oligomerization.
CC   -!- PTM: Polyneddylated. {ECO:0000269|PubMed:16111684}.
CC   -!- PTM: Not sumoylated. {ECO:0000250}.
CC   -!- PTM: Ubiquitinated at Lys-870 (By similarity). Polyubiquitinated.
CC       {ECO:0000250|UniProtKB:Q93009, ECO:0000269|PubMed:16111684,
CC       ECO:0000269|PubMed:16328052}.
CC   -!- SIMILARITY: Belongs to the peptidase C19 family. {ECO:0000305}.
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DR   EMBL; AY641530; AAT68666.1; -; mRNA.
DR   RefSeq; NP_001019961.1; NM_001024790.1.
DR   AlphaFoldDB; Q4VSI4; -.
DR   BMRB; Q4VSI4; -.
DR   SMR; Q4VSI4; -.
DR   BioGRID; 261960; 2.
DR   MINT; Q4VSI4; -.
DR   STRING; 10116.ENSRNOP00000041134; -.
DR   MEROPS; C19.016; -.
DR   iPTMnet; Q4VSI4; -.
DR   PhosphoSitePlus; Q4VSI4; -.
DR   jPOST; Q4VSI4; -.
DR   PaxDb; 10116-ENSRNOP00000041134; -.
DR   GeneID; 360471; -.
DR   KEGG; rno:360471; -.
DR   UCSC; RGD:1306915; rat.
DR   AGR; RGD:1306915; -.
DR   CTD; 7874; -.
DR   RGD; 1306915; Usp7.
DR   eggNOG; KOG1863; Eukaryota.
DR   InParanoid; Q4VSI4; -.
DR   OrthoDB; 51419at2759; -.
DR   PhylomeDB; Q4VSI4; -.
DR   Reactome; R-RNO-5689880; Ub-specific processing proteases.
DR   Reactome; R-RNO-6781823; Formation of TC-NER Pre-Incision Complex.
DR   Reactome; R-RNO-6782135; Dual incision in TC-NER.
DR   Reactome; R-RNO-6782210; Gap-filling DNA repair synthesis and ligation in TC-NER.
DR   Reactome; R-RNO-6804757; Regulation of TP53 Degradation.
DR   Reactome; R-RNO-8866652; Synthesis of active ubiquitin: roles of E1 and E2 enzymes.
DR   Reactome; R-RNO-8948747; Regulation of PTEN localization.
DR   PRO; PR:Q4VSI4; -.
DR   Proteomes; UP000002494; Unplaced.
DR   GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR   GO; GO:0005829; C:cytosol; ISO:RGD.
DR   GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR   GO; GO:0016605; C:PML body; ISO:RGD.
DR   GO; GO:0032991; C:protein-containing complex; ISO:RGD.
DR   GO; GO:0001741; C:XY body; ISO:RGD.
DR   GO; GO:0004843; F:cysteine-type deubiquitinase activity; IDA:RGD.
DR   GO; GO:0004197; F:cysteine-type endopeptidase activity; ISS:UniProtKB.
DR   GO; GO:0101005; F:deubiquitinase activity; ISS:UniProtKB.
DR   GO; GO:0042802; F:identical protein binding; IPI:RGD.
DR   GO; GO:1990380; F:K48-linked deubiquitinase activity; ISS:UniProtKB.
DR   GO; GO:0002039; F:p53 binding; ISO:RGD.
DR   GO; GO:0035616; P:histone H2B conserved C-terminal lysine deubiquitination; ISO:RGD.
DR   GO; GO:0035520; P:monoubiquitinated protein deubiquitination; ISO:RGD.
DR   GO; GO:0044027; P:negative regulation of gene expression via CpG island methylation; ISS:UniProtKB.
DR   GO; GO:0045721; P:negative regulation of gluconeogenesis; ISS:UniProtKB.
DR   GO; GO:0032435; P:negative regulation of proteasomal ubiquitin-dependent protein catabolic process; ISO:RGD.
DR   GO; GO:1904262; P:negative regulation of TORC1 signaling; ISO:RGD.
DR   GO; GO:0043065; P:positive regulation of apoptotic process; IDA:RGD.
DR   GO; GO:1901537; P:positive regulation of DNA demethylation; ISS:UniProtKB.
DR   GO; GO:0016579; P:protein deubiquitination; ISS:UniProtKB.
DR   GO; GO:0050821; P:protein stabilization; ISS:UniProtKB.
DR   GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR   GO; GO:0042752; P:regulation of circadian rhythm; ISS:UniProtKB.
DR   GO; GO:0051090; P:regulation of DNA-binding transcription factor activity; ISS:UniProtKB.
DR   GO; GO:0031647; P:regulation of protein stability; IDA:RGD.
DR   GO; GO:1905279; P:regulation of retrograde transport, endosome to Golgi; ISO:RGD.
DR   GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW.
DR   GO; GO:0075342; P:symbiont-mediated disruption of host cell PML body; ISO:RGD.
DR   GO; GO:0006283; P:transcription-coupled nucleotide-excision repair; ISS:UniProtKB.
DR   CDD; cd03772; MATH_HAUSP; 1.
DR   CDD; cd02659; peptidase_C19C; 1.
DR   Gene3D; 3.90.70.10; Cysteine proteinases; 1.
DR   InterPro; IPR002083; MATH/TRAF_dom.
DR   InterPro; IPR038765; Papain-like_cys_pep_sf.
DR   InterPro; IPR001394; Peptidase_C19_UCH.
DR   InterPro; IPR008974; TRAF-like.
DR   InterPro; IPR024729; USP7_ICP0-binding_dom.
DR   InterPro; IPR029346; USP_C.
DR   InterPro; IPR018200; USP_CS.
DR   InterPro; IPR028889; USP_dom.
DR   PANTHER; PTHR24006; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE; 1.
DR   PANTHER; PTHR24006:SF644; UBIQUITIN CARBOXYL-TERMINAL HYDROLASE 7; 1.
DR   Pfam; PF00917; MATH; 1.
DR   Pfam; PF00443; UCH; 1.
DR   Pfam; PF14533; USP7_C2; 1.
DR   Pfam; PF12436; USP7_ICP0_bdg; 1.
DR   SMART; SM00061; MATH; 1.
DR   SUPFAM; SSF54001; Cysteine proteinases; 1.
DR   SUPFAM; SSF49599; TRAF domain-like; 1.
DR   PROSITE; PS50144; MATH; 1.
DR   PROSITE; PS00972; USP_1; 1.
DR   PROSITE; PS00973; USP_2; 1.
DR   PROSITE; PS50235; USP_3; 1.
PE   1: Evidence at protein level;
KW   Acetylation; Biological rhythms; Chromosome; Cytoplasm;
KW   Developmental protein; DNA damage; DNA repair; Hydrolase; Isopeptide bond;
KW   Nucleus; Phosphoprotein; Protease; Reference proteome; Thiol protease;
KW   Ubl conjugation; Ubl conjugation pathway.
FT   CHAIN           1..1103
FT                   /note="Ubiquitin carboxyl-terminal hydrolase 7"
FT                   /id="PRO_0000268007"
FT   DOMAIN          69..196
FT                   /note="MATH"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00129"
FT   DOMAIN          215..522
FT                   /note="USP"
FT   REGION          1..209
FT                   /note="Interaction with TSPYL5"
FT                   /evidence="ECO:0000250|UniProtKB:Q93009"
FT   REGION          1..40
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          54..209
FT                   /note="Interaction with p53/TP53 and MDM2"
FT                   /evidence="ECO:0000250|UniProtKB:Q93009"
FT   REGION          71..206
FT                   /note="Necessary for nuclear localization"
FT                   /evidence="ECO:0000250|UniProtKB:Q93009"
FT   COMPBIAS        1..17
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        224
FT                   /note="Nucleophile"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10092,
FT                   ECO:0000255|PROSITE-ProRule:PRU10093,
FT                   ECO:0000269|PubMed:16111684, ECO:0000269|PubMed:16328052"
FT   ACT_SITE        465
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10092,
FT                   ECO:0000255|PROSITE-ProRule:PRU10093"
FT   MOD_RES         19
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:22673903"
FT   MOD_RES         50
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q6A4J8"
FT   MOD_RES         54
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q6A4J8"
FT   MOD_RES         870
FT                   /note="N6-acetyllysine; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:Q93009"
FT   MOD_RES         964
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q93009"
FT   MOD_RES         1085
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:Q93009"
FT   MOD_RES         1097
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:Q93009"
FT   CROSSLNK        870
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO2); alternate"
FT                   /evidence="ECO:0000250|UniProtKB:Q93009"
FT   CROSSLNK        870
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin); alternate"
FT                   /evidence="ECO:0000250|UniProtKB:Q93009"
FT   CROSSLNK        883
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO2)"
FT                   /evidence="ECO:0000250|UniProtKB:Q93009"
FT   MUTAGEN         224
FT                   /note="C->S: Loss of p53/TP53-deubiquitinating activity."
FT                   /evidence="ECO:0000269|PubMed:16111684,
FT                   ECO:0000269|PubMed:16328052"
SQ   SEQUENCE   1103 AA;  128431 MW;  A542C4149E241C7C CRC64;
     MNHQQQQQQQ QKAGEQQLSE PEDMEMEAGD TDDPPRITQN PVINGNVALS DGHSNAEEDM
     EDDTSWRSEA TFQFTVERFS RLSESVLSPP CFVRNLPWKI MVMPRFYPDR PHQKSVGFFL
     QCNAESDSTS WSCHAQAVLK IINYRDDDKS FSRRISHLFF HKENDWGFSN FMAWSEVTDP
     EKGFIDDDKV TFEVFVQADA PHGVAWDSKK HTGYVGLKNQ GATCYMNSLL QTLFFTNQLR
     KAVYMMPTEG DDSSKSVPLA LQRVFYELQH SDKPVGTKKL TKSFGWETLD SFMQHDVQEL
     CRVLLDNVEN KMKGTCVEGT IPKLFRGKMV SYIQCKEVDY RSDRREDYYD IQLSIKGKKN
     IFESFVDYVA VEQLDGDNKY DAGEHGLQEA EKGVKFLTLP PVLHLQLMRF MYDPQTDQNI
     KINDRFEFPE QLPLDEFLQK TDPKDPANYI LHAVLVHSGD NHGGHYVVYL NPKGDGKWCK
     FDDDVVSRCT KEEAIEHNYG GHDDDLSVRH CTNAYMLVYI RESKLSEVLQ AVTDHDIPQQ
     LVERLQEEKR IEAQKRKERQ EAHLYMQVQI VAEDQFCGHQ GNDMYDEEKV RYTVFKVLKN
     SSLAEFVQSL SQTMGFPQDQ IRLWPMQARS NGTKRPAMLD NEADGSKTMI ELSDNENPWT
     IFLETVDPEL AASGATLPKF DKDHDVMLFL KMYDPKTRSL NYCGHIYTPI SCKIRDLLPV
     MCDRAGFIQD TSLILYEEVK PNLTERIQDY DVSLDKALDE LMDGDIIVFQ KDDPENDNSE
     LPTAKEYFRD LYHRVDVIFC DKTIPNDPGF VVTLSNRMNY FQVAKTVAQR LNTDPMLLQF
     FKSQGYRDGP GNPLRHNYEG TLRDLLQFFK PRQPKKLYYQ QLKMKITDFE NRRSFKCIWL
     NSQFREEEIT LYPDKHGCVR DLLEECKKAV ELGDEASGRL RLLEIVSYKI IGVHQEDELL
     ECLSPATSRT FRIEEIPLDQ VNIDKENEML ITVAHFHKEV FGTFGIPFLL RIHQGEHFRE
     VMKRIQSLLD IQEKEFEKFK FAIVMMGRHQ YINEDEYEVN LKDFEPQPGN MSHPRPWLGL
     DHFNKAPKRS RYTYLEKAIK IHN
//