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

2008-09-01   Kwang-Hyun Baek , Suresh Ramakrishna 

Laboratory of Molecular Signal Transduction, Graduate School of Life Science, Biotechnology, Cell, Gene Therapy Research Institute, Pochon CHA university, CHA General Hospital, Seoul, Korea




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Consists of 31 Exons with a total transcription length of 4,013bps.


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.




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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.


HAUSP is expressed in wide variety of cell types including brain, liver, placenta, lung, ovary and melanocytes.


HAUSP primarily localized in Nucleus.


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.
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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.


Human HAUSP shows 98.6% amino acid homology with both rat HAUSP and mouse HAUSP.

Implicated in

Entity name
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 name
Herpes simplex
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 name
Cervical carcinoma
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 name
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 name
Non-small cell lung cancers and adenocarcinomas
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.
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.


Pubmed IDLast YearTitleAuthors
161601612005Reciprocal activities between herpes simplex virus type 1 regulatory protein ICP0, a ubiquitin E3 ligase, and ubiquitin-specific protease USP7.Boutell C et al
152472612004A RING finger ubiquitin ligase is protected from autocatalyzed ubiquitination and degradation by binding to ubiquitin-specific protease USP7.Canning M et al
165962372006HAUSP as a therapeutic target for hematopoietic tumors (review).Cheon KW et al
90343391997A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein.Everett RD et al
176514322007Biochemical characterization of USP7 reveals post-translational modification sites and structural requirements for substrate processing and subcellular localization.Fernández-Montalván A et al
154940002004HAUSP/USP7 as an Epstein-Barr virus target.Holowaty MN et al
120931612002USP7, a ubiquitin-specific protease, interacts with ataxin-1, the SCA1 gene product.Hong S et al
164028592006Structural basis of competitive recognition of p53 and MDM2 by HAUSP/USP7: implications for the regulation of the p53-MDM2 pathway.Hu M et al
125074302002Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde.Hu M et al
179272292007Proteome changes induced by knock-down of the deubiquitylating enzyme HAUSP/USP7.Kessler BM et al
150538802004A dynamic role of HAUSP in the p53-Mdm2 pathway.Li M et al
119238722002Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization.Li M et al
164503352006The HAUSP gene plays an important role in non-small cell lung carcinogenesis through p53-dependent pathways.Masuya D et al
159169632005Loss of HAUSP-mediated deubiquitination contributes to DNA damage-induced destabilization of Hdmx and Hdm2.Meulmeester E et al
149829962004Activity-based ubiquitin-specific protease (USP) profiling of virus-infected and malignant human cells.Ovaa H et al
99259441998Assignment1 of herpesvirus-associated ubiquitin-specific protease gene HAUSP to human chromosome band 16p13.3 by in situ hybridization.Robinson PA et al
164023892006Activity profiling of deubiquitinating enzymes in cervical carcinoma biopsies and cell lines.Rolén U et al
158085062005Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization.Saridakis V et al
164744022006Molecular recognition of p53 and MDM2 by USP7/HAUSP.Sheng Y et al
124136942002The ubiquitin-proteasome pathway in thymocyte apoptosis: caspase-dependent processing of the deubiquitinating enzyme USP7 (HAUSP).Vugmeyster Y et al
159426482005Expression and functional analyses of mHAUSP regulating apoptosis of cervical adenocarcinoma cells.Yoo KJ et al

Other Information

Locus ID:

NCBI: 7874
MIM: 602519
HGNC: 12630
Ensembl: ENSG00000187555


dbSNP: 7874
ClinVar: 7874
TCGA: ENSG00000187555


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Herpes simplex infectionKEGGko05168
Herpes simplex infectionKEGGhsa05168
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
Viral carcinogenesisKEGGhsa05203
Viral carcinogenesisKEGGko05203
FoxO signaling pathwayKEGGhsa04068
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Nucleotide Excision RepairREACTOMER-HSA-5696398
Transcription-Coupled Nucleotide Excision Repair (TC-NER)REACTOMER-HSA-6781827
Formation of TC-NER Pre-Incision ComplexREACTOMER-HSA-6781823
Dual incision in TC-NERREACTOMER-HSA-6782135
Gap-filling DNA repair synthesis and ligation in TC-NERREACTOMER-HSA-6782210
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Expression and DegradationREACTOMER-HSA-6806003
Regulation of TP53 DegradationREACTOMER-HSA-6804757
Ub-specific processing proteasesREACTOMER-HSA-5689880
Protein ubiquitinationREACTOMER-HSA-8852135
Synthesis of active ubiquitin: roles of E1 and E2 enzymesREACTOMER-HSA-8866652

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
119238722002Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization.328
150538802004A dynamic role of HAUSP in the p53-Mdm2 pathway.233
187166202008The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network.198
150582982004Tumour suppression: disruption of HAUSP gene stabilizes p53.125
159169632005Loss of HAUSP-mediated deubiquitination contributes to DNA damage-induced destabilization of Hdmx and Hdm2.120
158085062005Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization.117
164744022006Molecular recognition of p53 and MDM2 by USP7/HAUSP.99
214686932011The multifaceted roles of USP7: new therapeutic opportunities.98
219819252011Mechanism of USP7/HAUSP activation by its C-terminal ubiquitin-like domain and allosteric regulation by GMP-synthetase.81
194704782009Single-nucleotide polymorphisms in the p53 pathway regulate fertility in humans.66


Kwang-Hyun Baek ; Suresh Ramakrishna

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

Atlas Genet Cytogenet Oncol Haematol. 2008-09-01

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