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USP7 (ubiquitin specific peptidase 7 (herpes virus-associated))

Identity

Other namesEC 3.1.2.15
HAUSP
TEF1
HGNC (Hugo) USP7
LocusID (NCBI) 7874
Location 16p13.2
Location_base_pair Starts at 8985951 and ends at 9030586 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Gene is located on Chromosome 16 at 8, 894, 851-8, 964, 842.
Note Identified by its binding ability with Herpes simplex virus type 1 immediate-early protein Vmw 110 and Epstein-Barr nuclear antigen-1.

DNA/RNA

 
Description Consists of 31 Exons with a total transcription length of 4,013bps.
Transcription The coding region of the gene starts from exon 1 to exon 31 (200th bps to 3508th bps). The length of the transcript is 3308 bps.
Pseudogene None

Protein

 
Description HAUSP encodes for 1102 amino acids and its molecular weight is approximately 135kDa. MALDI-TOF/MS analysis has revealed four structural domains which are mainly involved in protein-protein interaction and deubiquitination activity.
N-terminal MATH (TRAF-like) domain (62-205aa) represented in brown colour is responsible for interaction with p53, MDM2 and EBNA1. N-terminal domain of USP7 complexed with Mdm2 at peptide 147-150 and with p53 at position 359-362 and 364-367 respectively.
Ubiquitin processing protease domain represented in yellow colour is a large family of cysteine proteases responsible for the cleavage of ubiquitin conjugates. Catalytic domain consists of approximately 350 amino acids, comprising three conserved domain architectures Finger, Palm, and Thumb. It has highly conserved Cys, Asp(I), His, and Asn/Asp(II) domains, which are responsible for deubiquitination activities.
ICP0 binding domain represented in green colour is located in the C-terminal region at position 599-801 amino acids. N-terminal polyglutamine (poly Q) region at position 4-10 amino acids which is conserved among mouse, rat and human.
Expression HAUSP is expressed in wide variety of cell types including brain, liver, placenta, lung, ovary and melanocytes.
Localisation HAUSP primarily localized in Nucleus.
Function Herpesvirus-associated ubiquitin-specific protease was identified as a novel p53-interacting protein. HAUSP binds and stabilizes p53 through deubiquitination. It also strongly interacts with MDM2, hence playing an important role in the p53-MDM2 pathway resulting in p53-dependent cell growth repression and apoptosis. The tumor suppressor p53 protein is a transcription factor that responds to many cellular stress signals and is regulated primarily through ubiquitination and subsequent degradation. HAUSP contains an N-terminal TRAF-like domain in which p53 and MDM2 binds at the same site implied that HAUSP may function as a tumor suppressor by stabilizing p53.
HAUSP also interacts with the Epstein-Barr nuclear antigen 1 (EBNA1) protein of the Epstein-Barr virus (EBV), which is responsible for EBV latent infection and cellular transformation. Interaction of EBNA1 with USP7 occurs at same N-terminal TRAF-like domain at which p53 also binds to USP7. Through interactions with p53, MDM2 and EBNA1, HAUSP plays a role in cell proliferation, apoptosis and EBV-mediated immortalization.
 
  A regulatory model controlling the stability of p53 and Mdm2 by HAUSP.
Note: HAUSP can deubiquitinate p53, Mdm2, and Mdmx. The selfubiquitination activity of Mdm2 is important to regulate both Mdm2 and p53 at opposite levels. Mdmx stabilizes Mdm2 by inhibiting self-ubiquitination. HAUSP plays a crucial role for regulating the levels of p53, Mdm2, and Mdmx.
Homology Human HAUSP shows 98.6% amino acid homology with both rat HAUSP and mouse HAUSP.

Implicated in

Entity Leukemia
Disease Several studies implicated that ubiquitin proteasome pathway plays a critical role in thymocyte apoptosis (Beyette et al., 1998). Upon induction of apoptosis in murine thymocytes, USP7 specifically processes dexamethasone and gamma irradiation induced cell death (Vugmeyster et al., 2002). High expression was found in thymus, spleen and brain, organs which rely on apoptosis for development. A similar observation was not observed in caspase 3-deficient thymocytes or thymocytes treated with general caspase inhibitors indicating caspase involvement in the process of apoptosis.
  
Entity Herpes simplex
Disease Herpes simplex virus type 1 immediate-early protein Vmw110 is a non-specific activator of gene expression and it is involved in the initiation of the viral lytic cycle. It has been demonstrated that USP7 interacts with Vmw 110 and its expression level is high during early infection (Everett et al., 1997). USP7 stabilizes herpes simplex virus type 1 regulatory protein ICP0 by its interaction during productive HSV-1 infection (Boutell et al., 2005).
  
Entity Cervical carcinoma
Disease A chemistry-based functional proteomics approach to identify individual USPs in human papillomavirus (HPV) carrying cervical carcinoma and adjacent normal tissue by biopsies showed high expression of USP7. Upregulation of USP7 in cervical carcinoma suggests its role in growth transformation (Rolen et al., 2006).
  
Entity Tumor
Disease USP7 was upregulated by mitogen activation or virus infection in normal T and B lymphocytes. USP7 expression was revealed by chemistry based functional proteomics approach in virus infected and tumor derived human cells (Ovaa et al., 2004). Holowaty and colleagues (2003) showed that USP7 interacts with Epstein-Barr nuclear antigen-1 (EBNA1) and involved in the regulation of EBNA1 replication activity. This findings suggests that USP7 has a critical role in EBV induced immortalization and tumorigenesis.
  
Entity Non-small cell lung cancers and adenocarcinomas
Note Most non-small cell lung cancers (NSCLCs) shows a reduced herpesvirus-associated ubiquitin-specific protease expression. Therefore, the HAUSP gene might play an important role in carcinogenesis.
Disease Quantitative reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry were performed to evaluate the protein expression of HAUSP in several patients with non-small cell lung cancer (NSCLC) (Masuya et al., 2006). Fifty-nine carcinomas (45.0%) showed reduced expression of HAUSP and HAUSP mRNA expression was significantly lower in adenocarcinomas and squamous cell carcinomas. In total, 93 carcinomas (71.0%) showed either mutant p53 or reduced HAUSP expression. The down-regulation of USP7 affects the p53 protein expression which in turn leads to tumors. These data show the importance of USP7 expression in NSCLC carcinogenesis, especially in adenocarcinomas.
  

External links

Nomenclature
HGNC (Hugo)USP7   12630
Cards
AtlasUSP7ID42773ch16p13
Entrez_Gene (NCBI)USP7  7874  ubiquitin specific peptidase 7 (herpes virus-associated)
GeneCards (Weizmann)USP7
Ensembl (Hinxton)ENSG00000187555 [Gene_View]  chr16:8985951-9030586 [Contig_View]  USP7 [Vega]
ICGC DataPortalENSG00000187555
cBioPortalUSP7
AceView (NCBI)USP7
Genatlas (Paris)USP7
WikiGenes7874
SOURCE (Princeton)NM_001286457 NM_001286458 NM_003470
Genomic and cartography
GoldenPath (UCSC)USP7  -  16p13.2   chr16:8985951-9030586 -  16p13.3   [Description]    (hg19-Feb_2009)
EnsemblUSP7 - 16p13.3 [CytoView]
Mapping of homologs : NCBIUSP7 [Mapview]
OMIM602519   
Gene and transcription
Genbank (Entrez)AK302481 AK302771 AK302872 AK302912 AK316441
RefSeq transcript (Entrez)NM_001286457 NM_001286458 NM_003470
RefSeq genomic (Entrez)AC_000148 NC_000016 NC_018927 NT_010393 NW_001838342 NW_004929400
Consensus coding sequences : CCDS (NCBI)USP7
Cluster EST : UnigeneHs.386939 [ NCBI ]
CGAP (NCI)Hs.386939
Alternative Splicing : Fast-db (Paris)GSHG0011611
Alternative Splicing GalleryENSG00000187555
Gene ExpressionUSP7 [ NCBI-GEO ]     USP7 [ SEEK ]   USP7 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ93009 (Uniprot)
NextProtQ93009  [Medical]
With graphics : InterProQ93009
Splice isoforms : SwissVarQ93009 (Swissvar)
Catalytic activity : Enzyme3.4.19.12 [ Enzyme-Expasy ]   3.4.19.123.4.19.12 [ IntEnz-EBI ]   3.4.19.12 [ BRENDA ]   3.4.19.12 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)MATH (PS50144)    USP_1 (PS00972)    USP_2 (PS00973)    USP_3 (PS50235)   
Domains : Interpro (EBI)MATH [organisation]   Pept_C19ubi-hydrolase_C_CS [organisation]   Peptidase_C19_UCH [organisation]   TRAF-like [organisation]   UCH/PAN2 [organisation]   USP7_ICP0-binding_dom [organisation]   USP_C [organisation]  
Related proteins : CluSTrQ93009
Domain families : Pfam (Sanger)MATH (PF00917)    UCH (PF00443)    USP7_C2 (PF14533)    USP7_ICP0_bdg (PF12436)   
Domain families : Pfam (NCBI)pfam00917    pfam00443    pfam14533    pfam12436   
Domain families : Smart (EMBL)MATH (SM00061)  
DMDM Disease mutations7874
Blocks (Seattle)Q93009
PDB (SRS)1NB8    1NBF    1YY6    1YZE    2F1W    2F1X    2F1Y    2F1Z    2FOJ    2FOO    2FOP    2KVR    2XXN    2YLM    3MQR    3MQS    4JJQ    4KG9    4M5W    4M5X    4PYZ   
PDB (PDBSum)1NB8    1NBF    1YY6    1YZE    2F1W    2F1X    2F1Y    2F1Z    2FOJ    2FOO    2FOP    2KVR    2XXN    2YLM    3MQR    3MQS    4JJQ    4KG9    4M5W    4M5X    4PYZ   
PDB (IMB)1NB8    1NBF    1YY6    1YZE    2F1W    2F1X    2F1Y    2F1Z    2FOJ    2FOO    2FOP    2KVR    2XXN    2YLM    3MQR    3MQS    4JJQ    4KG9    4M5W    4M5X    4PYZ   
PDB (RSDB)1NB8    1NBF    1YY6    1YZE    2F1W    2F1X    2F1Y    2F1Z    2FOJ    2FOO    2FOP    2KVR    2XXN    2YLM    3MQR    3MQS    4JJQ    4KG9    4M5W    4M5X    4PYZ   
Human Protein AtlasENSG00000187555 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasQ93009
HPRD03950
IPIIPI00003965   IPI01009317   IPI00646721   IPI00922910   IPI01011924   
Protein Interaction databases
DIP (DOE-UCLA)Q93009
IntAct (EBI)Q93009
FunCoupENSG00000187555
BioGRIDUSP7
InParanoidQ93009
Interologous Interaction database Q93009
IntegromeDBUSP7
STRING (EMBL)USP7
Ontologies - Pathways
Ontology : AmiGOp53 binding  cysteine-type endopeptidase activity  ubiquitin thiolesterase activity  ubiquitin thiolesterase activity  ubiquitin-specific protease activity  ubiquitin-specific protease activity  protein binding  nucleus  cytosol  transcription-coupled nucleotide-excision repair  ubiquitin-dependent protein catabolic process  multicellular organismal development  protein C-terminus binding  transcription factor binding  maintenance of DNA methylation  viral process  protein deubiquitination  protein deubiquitination  PML body  ubiquitin protein ligase binding  negative regulation of NF-kappaB transcription factor activity  regulation of sequence-specific DNA binding transcription factor activity  
Ontology : EGO-EBIp53 binding  cysteine-type endopeptidase activity  ubiquitin thiolesterase activity  ubiquitin thiolesterase activity  ubiquitin-specific protease activity  ubiquitin-specific protease activity  protein binding  nucleus  cytosol  transcription-coupled nucleotide-excision repair  ubiquitin-dependent protein catabolic process  multicellular organismal development  protein C-terminus binding  transcription factor binding  maintenance of DNA methylation  viral process  protein deubiquitination  protein deubiquitination  PML body  ubiquitin protein ligase binding  negative regulation of NF-kappaB transcription factor activity  regulation of sequence-specific DNA binding transcription factor activity  
Pathways : KEGGFoxO signaling pathway    Herpes simplex infection    Epstein-Barr virus infection    Viral carcinogenesis   
Protein Interaction DatabaseUSP7
Wikipedia pathwaysUSP7
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)USP7
snp3D : Map Gene to Disease7874
SNP (GeneSNP Utah)USP7
SNP : HGBaseUSP7
Genetic variants : HAPMAPUSP7
Exome VariantUSP7
1000_GenomesUSP7 
ICGC programENSG00000187555 
Somatic Mutations in Cancer : COSMICUSP7 
CONAN: Copy Number AnalysisUSP7 
Mutations and Diseases : HGMDUSP7
Genomic VariantsUSP7  USP7 [DGVbeta]
dbVarUSP7
ClinVarUSP7
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM602519   
MedgenUSP7
GENETestsUSP7
Disease Genetic AssociationUSP7
Huge Navigator USP7 [HugePedia]  USP7 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneUSP7
Homology/Alignments : Family Browser (UCSC)USP7
Phylogenetic Trees/Animal Genes : TreeFamUSP7
Chemical/Protein Interactions : CTD7874
Chemical/Pharm GKB GenePA37255
Clinical trialUSP7
Cancer Resource (Charite)ENSG00000187555
Other databases
Probes
Litterature
PubMed148 Pubmed reference(s) in Entrez
CoreMineUSP7
iHOPUSP7
OncoSearchUSP7

Bibliography

A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein.
Everett RD, Meredith M, Orr A, Cross A, Kathoria M, Parkinson J.
EMBO J. 1997 Apr 1;16(7):1519-30.
PMID 9034339
 
Assignment1 of herpesvirus-associated ubiquitin-specific protease gene HAUSP to human chromosome band 16p13.3 by in situ hybridization.
Robinson PA, Lomonte P, Leek , Markham AF, Everett RD.
Cytogenet Cell Genet. 1998;83(1-2):100.
PMID 9925944
 
USP7, a ubiquitin-specific protease, interacts with ataxin-1, the SCA1 gene product.
Hong S, Kim SJ, Ka S, Choi I, Kang S.
Mol Cell Neurosci. 2002 Jun;20(2):298-306.
PMID 12093161
 
Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde.
Hu M, Li P, Li M, Li W, Yao T, Wu JW, Gu W, Cohen RE, Shi Y.
Cell. 2002 Dec 27;111(7):1041-54.
PMID 12507430
 
Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization.
Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J, Gu W.
Nature. 2002 Apr 11;416(6881):648-53. Epub 2002 Mar 31.
PMID 11923872
 
The ubiquitin-proteasome pathway in thymocyte apoptosis: caspase-dependent processing of the deubiquitinating enzyme USP7 (HAUSP).
Vugmeyster Y, Borodovsky A, Maurice MM, Maehr R, Furman MH, Ploegh HL.
Mol Immunol. 2002 Nov;39(7-8):431-41.
PMID 12413694
 
Protein interaction domains of the ubiquitin-specific protease, USP7/HAUSP.
Holowaty MN, Sheng Y, Nguyen T, Arrowsmith C, Frappier L.
J Biol Chem. 2003 Nov 28;278(48):47753-61. Epub 2003 Sep 23.
PMID 14506283
 
Protein profiling with Epstein-Barr nuclear antigen-1 reveals an interaction with the herpesvirus-associated ubiquitin-specific protease HAUSP/USP7.
Holowaty MN, Zeghouf M, Wu H, Tellam J, Athanasopoulos V, Greenblatt J, Frappier L.
J Biol Chem. 2003 Aug 8;278(32):29987-94. Epub 2003 Jun 3.
PMID 12783858
 
A RING finger ubiquitin ligase is protected from autocatalyzed ubiquitination and degradation by binding to ubiquitin-specific protease USP7.
Canning M, Boutell C, Parkinson J, Everett RD.
J Biol Chem. 2004 Sep 10;279(37):38160-8. Epub 2004 Jul 6.
PMID 15247261
 
HAUSP/USP7 as an Epstein-Barr virus target.
Holowaty MN, Frappier L.
Biochem Soc Trans. 2004 Nov;32(Pt 5):731-2. (REVIEW)
PMID 15494000
 
A dynamic role of HAUSP in the p53-Mdm2 pathway.
Li M, Brooks CL, Kon N, Gu W.
Mol Cell. 2004 Mar 26;13(6):879-86.
PMID 15053880
 
Activity-based ubiquitin-specific protease (USP) profiling of virus-infected and malignant human cells.
Ovaa H, Kessler BM, Rolen U, Galardy PJ, Ploegh HL, Masucci MG.
Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2253-8.
PMID 14982996
 
Reciprocal activities between herpes simplex virus type 1 regulatory protein ICP0, a ubiquitin E3 ligase, and ubiquitin-specific protease USP7.
Boutell C, Canning M, Orr A, Everett RD.
J Virol. 2005 Oct;79(19):12342-54.
PMID 16160161
 
Loss of HAUSP-mediated deubiquitination contributes to DNA damage-induced destabilization of Hdmx and Hdm2.
Meulmeester E, Maurice MM, Boutell C, Teunisse AF, Ovaa H, Abraham TE, Dirks RW, Jochemsen AG.
Mol Cell. 2005 May 27;18(5):565-76.
PMID 15916963
 
Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization.
Saridakis V, Sheng Y, Sarkari F, Holowaty MN, Shire K, Nguyen T, Zhang RG, Liao J, Lee W, Edwards AM, Arrowsmith CH, Frappier L.
Mol Cell. 2005 Apr 1;18(1):25-36.
PMID 15808506
 
Expression and functional analyses of mHAUSP regulating apoptosis of cervical adenocarcinoma cells.
Yoo KJ, Lee HJ, Lee H, Lee KY, Lee SH, Chung HM, Baek KH.
Int J Oncol. 2005 Jul;27(1):97-104.
PMID 15942648
 
HAUSP as a therapeutic target for hematopoietic tumors
Cheon KW, Baek KH.
Int J Oncol. 2006 May;28(5):1209-15. (REVIEW)
PMID 16596237
 
Structural basis of competitive recognition of p53 and MDM2 by HAUSP/USP7: implications for the regulation of the p53-MDM2 pathway.
Hu M, Gu L, Li M, Jeffrey PD, Gu W, Shi Y.
PLoS Biol. 2006 Feb;4(2):e27. Epub 2006 Jan 17.
PMID 16402859
 
The HAUSP gene plays an important role in non-small cell lung carcinogenesis through p53-dependent pathways.
Masuya D, Huang C, Liu D, Nakashima T, Yokomise H, Ueno M, Nakashima N, Sumitomo S.
J Pathol. 2006 Apr;208(5):724-32.
PMID 16450335
 
Activity profiling of deubiquitinating enzymes in cervical carcinoma biopsies and cell lines.
Rolen U, Kobzeva V, Gasparjan N, Ovaa H, Winberg G, Kisseljov F, Masucci MG.
Mol Carcinog. 2006 Apr;45(4):260-9.
PMID 16402389
 
Molecular recognition of p53 and MDM2 by USP7/HAUSP.
Sheng Y, Saridakis V, Sarkari F, Duan S, Wu T, Arrowsmith CH, Frappier L.
Nat Struct Mol Biol. 2006 Mar;13(3):285-91. Epub 2006 Feb 12.
PMID 16474402
 
Biochemical characterization of USP7 reveals post-translational modification sites and structural requirements for substrate processing and subcellular localization.
Fernandez-Montalvan A, Bouwmeester T, Joberty G, Mader R, Mahnke M, Pierrat B, Schlaeppi JM, Worpenberg S, Gerhartz B.
FEBS J. 2007 Aug;274(16):4256-70. Epub 2007 Jul 25.
PMID 17651432
 
Proteome changes induced by knock-down of the deubiquitylating enzyme HAUSP/USP7.
Kessler BM, Fortunati E, Melis M, Pals CE, Clevers H, Maurice MM.
J Proteome Res. 2007 Nov;6(11):4163-72. Epub 2007 Oct 10.
PMID 17927229
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written09-2008Kwang-Hyun Baek, Suresh Ramakrishna
Laboratory of Molecular Signal Transduction, Graduate School of Life Science and Biotechnology, Cell and Gene Therapy Research Institute, Pochon CHA university, CHA General Hospital, Seoul, Korea

Citation

This paper should be referenced as such :
Baek, KH ; Ramakrishna, S
USP7 (ubiquitin specific peptidase 7 (herpes virus-associated))
Atlas Genet Cytogenet Oncol Haematol. 2009;13(8):576-579.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/USP7ID42773ch16p13.html

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indexed on : Wed Jul 30 16:55:47 CEST 2014

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