USP7

Ubiquitin specific peptidase 7 (herpes virus-associated), also known as USP7, is a human gene.cite web | title = Entrez Gene: USP7 ubiquitin specific peptidase 7 (herpes virus-associated)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7874| accessdate = ] cite journal | author = Everett RD, Meredith M, Orr A, Cross A, Kathoria M, Parkinson J | title = A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein | journal = EMBO J. | volume = 16 | issue = 7 | pages = 1519–30 | year = 1997 | month = April | pmid = 9130697 | pmc = 1169756 | doi = 10.1093/emboj/16.7.1519 | url = | issn = ]

Function

USP7 or HAUSP is a ubiquitin specific protease or a deubiquitylating enzyme that cleaves ubiquitin from its substrates.cite journal | author = Holowaty MN, Sheng Y, Nguyen T, Arrowsmith C, Frappier L | title = Protein interaction domains of the ubiquitin-specific protease, USP7/HAUSP | journal = J. Biol. Chem. | volume = 278 | issue = 48 | pages = 47753–61 | year = 2003 | month = November | pmid = 14506283 | doi = 10.1074/jbc.M307200200 | url = | issn = ] Since ubiquitylation (polyubiquitination) is most commonly associated with the stability and degradation of cellular proteins, HAUSP acitivity generally stabilizes its substrate proteins. HAUSP is most popularly known as a direct antagonist of Mdm2, the E3 ubiquitin ligase for the tumor suppressor protein, p53.cite journal | author = Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J, Gu W | title = Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization | journal = Nature | volume = 416 | issue = 6881 | pages = 648–53 | year = 2002 | month = April | pmid = 11923872 | doi = 10.1038/nature737 | url = | issn = ] Normally, p53 levels are kept low in part due to Mdm2-mediated ubiquitylation and degradation of p53. Interestingly, in response to oncogenic insults, HAUSP can deubiquitinate p53 and protect p53 from Mdm2-mediated degradation, indicating that it may possess a tumor suppressor function for the immediate stabilization of p53 in response to stress. Another important role of HAUSP function involves the oncogenic stabilization of p53. Oncogenes such as Myc and E1A are thought to activate p53 through a p19 alternative reading frame (p19ARF, also called ARF)-dependent pathway, although some evidence suggests ARF is not essential in this process. An intriguing possibility is that HAUSP provides an alternative pathway for safeguarding the cell against oncogenic insults.

Association with herpesviruses

USP7 was originally identified as a protein associated with the ICP0 protein of herpes simplex virus (HSV), hence the name Herpesvirus Associated USP (HAUSP). ICP0 is an E3-ubiquitin ligase that is involved in ubiquitination and subsequent degradation of itself and certain cellular proteins. USP7 has been shown to regulate the auto-ubiquitination and degradation of ICP0.

More recently, an interaction between USP7 and the EBNA1 protein of Epstein-Barr virus (EBV) (another herpesvirus) was also discovered.cite journal | author = Holowaty MN, Frappier L | title = HAUSP/USP7 as an Epstein-Barr virus target | journal = Biochem. Soc. Trans. | volume = 32 | issue = Pt 5 | pages = 731–2 | year = 2004 | month = November | pmid = 15494000 | doi = 10.1042/BST0320731 | url = | issn = ] This interaction is particularly interesting given the oncogenic potential (potential to cause cancer) of EBV, which is associated with several human cancers. EBNA1 can compete with p53 for binding USP7. Stabilization by USP7 is important for the tumor suppressor function of p53. In cells, EBNA1 can sequester USP7 from p53 and thus attenuate stabilization of p53, rendering the cells predisposed to turning cancerous. Compromising the function of p53 by sequestering USP7 is one way EBNA1 can contribute to the oncogenic potential of EBV.

The fact that viral proteins have evolved so as to target USP7, underscores the significance of USP7 in tumor suppression and other cellular processes.

Binding partners

The following is a list of some of the known cellular binding partners of USP7/HAUSP:

* p53
* Mdm2
* Mdm4/MdmX
* FOXO4
* Daxx
* PTEN
* March7

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=D'Andrea A, Pellman D |title=Deubiquitinating enzymes: a new class of biological regulators. |journal=Crit. Rev. Biochem. Mol. Biol. |volume=33 |issue= 5 |pages= 337–52 |year= 1999 |pmid= 9827704 |doi=
*cite journal | author=Puente XS, Sánchez LM, Overall CM, López-Otín C |title=Human and mouse proteases: a comparative genomic approach. |journal=Nat. Rev. Genet. |volume=4 |issue= 7 |pages= 544–58 |year= 2003 |pmid= 12838346 |doi= 10.1038/nrg1111
*cite journal | author=Holowaty MN, Frappier L |title=HAUSP/USP7 as an Epstein-Barr virus target. |journal=Biochem. Soc. Trans. |volume=32 |issue= Pt 5 |pages= 731–2 |year= 2005 |pmid= 15494000 |doi= 10.1042/BST0320731
*cite journal | author=Everett RD, Meredith M, Orr A, "et al." |title=A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein. |journal=EMBO J. |volume=16 |issue= 3 |pages= 566–77 |year= 1997 |pmid= 9034339 |doi= 10.1093/emboj/16.3.566
*cite journal | author=Everett RD, Meredith M, Orr A, "et al." |title=A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein. |journal=EMBO J. |volume=16 |issue= 7 |pages= 1519–30 |year= 1997 |pmid= 9130697 |doi= 10.1093/emboj/16.7.1519
*cite journal | author=Robinson PA, Lomonte P, Leek, "et al." |title=Assignment1 of herpesvirus-associated ubiquitin-specific protease gene HAUSP to human chromosome band 16p13.3 by in situ hybridization. |journal=Cytogenet. Cell Genet. |volume=83 |issue= 1-2 |pages= 100 |year= 1999 |pmid= 9925944 |doi=
*cite journal | author=Zapata JM, Pawlowski K, Haas E, "et al." |title=A diverse family of proteins containing tumor necrosis factor receptor-associated factor domains. |journal=J. Biol. Chem. |volume=276 |issue= 26 |pages= 24242–52 |year= 2001 |pmid= 11279055 |doi= 10.1074/jbc.M100354200
*cite journal | author=Li M, Chen D, Shiloh A, "et al." |title=Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. |journal=Nature |volume=416 |issue= 6881 |pages= 648–53 |year= 2002 |pmid= 11923872 |doi= 10.1038/nature737
*cite journal | author=Hong S, Kim SJ, Ka S, "et al." |title=USP7, a ubiquitin-specific protease, interacts with ataxin-1, the SCA1 gene product. |journal=Mol. Cell. Neurosci. |volume=20 |issue= 2 |pages= 298–306 |year= 2002 |pmid= 12093161 |doi=
*cite journal | author=Hu M, Li P, Li M, "et al." |title=Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde. |journal=Cell |volume=111 |issue= 7 |pages= 1041–54 |year= 2003 |pmid= 12507430 |doi=
*cite journal | author=Holowaty MN, Sheng Y, Nguyen T, "et al." |title=Protein interaction domains of the ubiquitin-specific protease, USP7/HAUSP. |journal=J. Biol. Chem. |volume=278 |issue= 48 |pages= 47753–61 |year= 2004 |pmid= 14506283 |doi= 10.1074/jbc.M307200200
*cite journal | author=Brajenovic M, Joberty G, Küster B, "et al." |title=Comprehensive proteomic analysis of human Par protein complexes reveals an interconnected protein network. |journal=J. Biol. Chem. |volume=279 |issue= 13 |pages= 12804–11 |year= 2004 |pmid= 14676191 |doi= 10.1074/jbc.M312171200
*cite journal | author=Li M, Brooks CL, Kon N, Gu W |title=A dynamic role of HAUSP in the p53-Mdm2 pathway. |journal=Mol. Cell |volume=13 |issue= 6 |pages= 879–86 |year= 2004 |pmid= 15053880 |doi=
*cite journal | author=Cummins JM, Rago C, Kohli M, "et al." |title=Tumour suppression: disruption of HAUSP gene stabilizes p53. |journal=Nature |volume=428 |issue= 6982 |pages= 1 p following 486 |year= 2004 |pmid= 15058298 |doi= 10.1038/nature02501
*cite journal | author=Canning M, Boutell C, Parkinson J, Everett RD |title=A RING finger ubiquitin ligase is protected from autocatalyzed ubiquitination and degradation by binding to ubiquitin-specific protease USP7. |journal=J. Biol. Chem. |volume=279 |issue= 37 |pages= 38160–8 |year= 2004 |pmid= 15247261 |doi= 10.1074/jbc.M402885200
*cite journal | author=Beausoleil SA, Jedrychowski M, Schwartz D, "et al." |title=Large-scale characterization of HeLa cell nuclear phosphoproteins. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue= 33 |pages= 12130–5 |year= 2004 |pmid= 15302935 |doi= 10.1073/pnas.0404720101
*cite journal | author=Saridakis V, Sheng Y, Sarkari F, "et al." |title=Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization. |journal=Mol. Cell |volume=18 |issue= 1 |pages= 25–36 |year= 2005 |pmid= 15808506 |doi= 10.1016/j.molcel.2005.02.029

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