Download Gene Section USP7 (ubiquitin specific peptidase 7 (herpes virus- associated))

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in Oncology and Haematology
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Gene Section
Mini Review
USP7 (ubiquitin specific peptidase 7 (herpes virusassociated))
Kwang-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 (KHB, SR)
Published in Atlas Database: September 2008
Online updated version : http://AtlasGeneticsOncology.org/Genes/USP7ID42773ch16p13.html
DOI: 10.4267/2042/44538
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Protein
Other names: EC 3.1.2.15; HAUSP; TEF1
HGNC (Hugo): USP7
Location: 16p13.3
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.
Description
HAUSP encodes for 1102 amino acids and its
molecular weight is approximately 135 kDa. MALDITOF/MS analysis has revealed four structural domains
which are mainly involved in protein-protein
interaction and deubiquitination activity.
N-terminal MATH (TRAF-like) domain (62-205 aa)
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.
DNA/RNA
Description
Consists of 31 exons with a total transcription length of
4,013 bps.
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.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(8)
576
USP7 (ubiquitin specific peptidase 7 (herpes virus-associated))
Baek KH, Ramakrishna S
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.
apoptosis and EBV-mediated immortalization.
Homology
Human HAUSP shows 98.6% amino acid homology
with both rat HAUSP and mouse HAUSP.
Expression
Implicated in
HAUSP is expressed in wide variety of cell types
including brain, liver, placenta, lung, ovary and
melanocytes.
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.
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 Nterminal 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,
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(8)
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).
577
USP7 (ubiquitin specific peptidase 7 (herpes virus-associated))
Baek KH, Ramakrishna S
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.
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.
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).
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.
References
Everett RD, 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. 1997 Feb 3;16(3):566-77
Non-small cell lung cancers and
adenocarcinomas
Robinson PA, Lomonte P, Leek, Markham AF, Everett RD.
Assignment1 of herpesvirus-associated ubiquitin-specific
protease gene HAUSP to human chromosome band 16p13.3
by in situ hybridization. Cytogenet Cell Genet. 1998;83(12):100
Note
Most non-small cell lung cancers (NSCLCs) show a
reduced
herpesvirus-associated
ubiquitin-specific
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(8)
578
USP7 (ubiquitin specific peptidase 7 (herpes virus-associated))
Baek KH, Ramakrishna S
Hong S, Kim SJ, Ka S, Choi I, Kang S. USP7, a ubiquitinspecific protease, interacts with ataxin-1, the SCA1 gene
product. Mol Cell Neurosci. 2002 Jun;20(2):298-306
Saridakis V, Sheng Y, Sarkari F, Holowaty MN, Shire K,
Nguyen T, Zhang RG, Liao J, Lee W, Edwards AM, Arrowsmith
CH, Frappier L. Structure of the p53 binding domain of
HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1
implications for EBV-mediated immortalization. Mol Cell. 2005
Apr 1;18(1):25-36
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isolation and in complex with ubiquitin aldehyde. Cell. 2002
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KH. Expression and functional analyses of mHAUSP regulating
apoptosis of cervical adenocarcinoma cells. Int J Oncol. 2005
Jul;27(1):97-104
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Deubiquitination of p53 by HAUSP is an important pathway for
p53 stabilization. Nature. 2002 Apr 11;416(6881):648-53
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hematopoietic tumors (review). Int J Oncol. 2006
May;28(5):1209-15
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MH, Ploegh HL. The ubiquitin-proteasome pathway in
thymocyte apoptosis: caspase-dependent processing of the
deubiquitinating enzyme USP7 (HAUSP). Mol Immunol. 2002
Nov;39(7-8):431-41
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competitive recognition of p53 and MDM2 by HAUSP/USP7:
implications for the regulation of the p53-MDM2 pathway.
PLoS Biol. 2006 Feb;4(2):e27
Holowaty MN, Sheng Y, Nguyen T, Arrowsmith C, Frappier L.
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M, Nakashima N, Sumitomo S. The HAUSP gene plays an
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p53-dependent pathways. J Pathol. 2006 Apr;208(5):724-32
Holowaty MN, Zeghouf M, Wu H, Tellam J, Athanasopoulos V,
Greenblatt J, Frappier L. Protein profiling with Epstein-Barr
nuclear antigen-1 reveals an interaction with the herpesvirusassociated ubiquitin-specific protease HAUSP/USP7. J Biol
Chem. 2003 Aug 8;278(32):29987-94
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ubiquitin ligase is protected from autocatalyzed ubiquitination
and degradation by binding to ubiquitin-specific protease
USP7. J Biol Chem. 2004 Sep 10;279(37):38160-8
Sheng Y, Saridakis V, Sarkari F, Duan S, Wu T, Arrowsmith
CH, Frappier L. Molecular recognition of p53 and MDM2 by
USP7/HAUSP. Nat Struct Mol Biol. 2006 Mar;13(3):285-91
Holowaty MN, Frappier L. HAUSP/USP7 as an Epstein-Barr
virus target. Biochem Soc Trans. 2004 Nov;32(Pt 5):731-2
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Mahnke M, Pierrat B, Schlaeppi JM, Worpenberg S, Gerhartz
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2007 Aug;274(16):4256-70
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the p53-Mdm2 pathway. Mol Cell. 2004 Mar 26;13(6):879-86
Ovaa H, Kessler BM, Rolén U, Galardy PJ, Ploegh HL,
Masucci MG. Activity-based ubiquitin-specific protease (USP)
profiling of virus-infected and malignant human cells. Proc Natl
Acad Sci U S A. 2004 Feb 24;101(8):2253-8
Kessler BM, Fortunati E, Melis M, Pals CE, Clevers H, Maurice
MM. Proteome changes induced by knock-down of the
deubiquitylating enzyme HAUSP/USP7. J Proteome Res. 2007
Nov;6(11):4163-72
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This article 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.
Meulmeester E, Maurice MM, Boutell C, Teunisse AF, Ovaa H,
Abraham TE, Dirks RW, Jochemsen AG. Loss of HAUSPmediated deubiquitination contributes to DNA damage-induced
destabilization of Hdmx and Hdm2. Mol Cell. 2005 May
27;18(5):565-76
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