| Written | 2008-09 | 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 |
| Identity |
| Alias_names | HAUSP |
| ubiquitin specific peptidase 7 (herpes virus-associated) | |
| Other alias | EC 3.1.2.15 |
| TEF1 | |
| HGNC (Hugo) | USP7 |
| LocusID (NCBI) | 7874 |
| Atlas_Id | 42773 |
| Location | 16p13.2 [Link to chromosome band 16p13] |
| Location_base_pair | Starts at 8892094 and ends at 8963484 bp from pter ( according to hg19-Feb_2009) [Mapping USP7.png] |
| Local_order | Gene is located on Chromosome 16 at 8, 894, 851-8, 964, 842. |
| Fusion genes (updated 2017) | Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands) |
| GATAD2B (1q21.3) / USP7 (16p13.2) | PKM (15q23) / USP7 (16p13.2) |
| 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 |
| Note | |
| 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. |
| Bibliography |
| 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 |
| 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 as a therapeutic target for hematopoietic tumors |
| Cheon KW, Baek KH. |
| Int J Oncol. 2006 May;28(5):1209-15. (REVIEW) |
| PMID 16596237 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| 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 journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Genes/USP7ID42773ch16p13.html |
| Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ] |
|
t(14;16)(q11;p13) USP7/TRA
|
| Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ] |
|
t(15;16)(q23;p13) PKM/USP7
|
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Wed Nov 13 22:09:23 CET 2019 |
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