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Gene Review

USP7  -  ubiquitin specific peptidase 7 (herpes...

Homo sapiens

Synonyms: Deubiquitinating enzyme 7, HAUSP, Herpesvirus-associated ubiquitin-specific protease, TEF1, Ubiquitin carboxyl-terminal hydrolase 7, ...
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Disease relevance of USP7

  • Reciprocal activities between herpes simplex virus type 1 regulatory protein ICP0, a ubiquitin E3 ligase, and ubiquitin-specific protease USP7 [1].
  • Based on a thorough analysis of the properties of an HSV-1 mutant virus that expresses forms of ICP0 that are unable to bind to USP7, we conclude that USP7-mediated stabilization of ICP0 is dominant over ICP0-induced degradation of USP7 during productive HSV-1 infection [1].
  • HAUSP/USP7 as an Epstein-Barr virus target [2].
  • In total, 93 carcinomas (71.0%) showed either mutant p53 or reduced HAUSP expression [3].
  • In addition, the simultaneous evaluation of both HAUSP expression and p53 gene status was a significant indicator of poor prognosis in adenocarcinoma patients (hazard ratio 4.840, p = 0.0357) [3].

High impact information on USP7

  • Here, we report the crystal structures of the 40 kDa catalytic core domain of HAUSP in isolation and in complex with ubiquitin aldehyde [4].
  • The HeLa cell protein TEF-1 binds specifically and cooperatively to two SV40 enhancer motifs of unrelated sequence [5].
  • In contrast, TEF-1 and a second SV40 enhancer binding protein, TEF-2, bind independently to templates containing the cognate motifs of both proteins (GT-I and either GT-IIC or Sph motifs) even though these motifs cooperate in enhancer activity in vivo [5].
  • These findings reveal an important mechanism by which p53 can be stabilized by direct deubiquitination and also imply that HAUSP might function as a tumour suppressor in vivo through the stabilization of p53 [6].
  • Similar to USP7, mutations in GMPS acted as enhancers of Pc in vivo [7].

Biological context of USP7


Anatomical context of USP7


Associations of USP7 with chemical compounds

  • Contacts made by serine are identical and crucial for all peptides, and Trp165 in the peptide-binding pocket of USP7 is also crucial [10].
  • We purified USP7 from embryo nuclear extracts as a stable heteromeric complex with guanosine 5'-monophosphate synthetase (GMPS) [7].
  • While the majority of these changes were silent, TEF-2 and TEF-3 differed from TEF-1 by having a lysine instead of a glutamate at amino acid position 41 [14].

Physical interactions of USP7

  • Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization [15].
  • Using mutant Vmw110 viruses we show that the RING finger domain of Vmw110 is essential for the induced degradation of DNA-PKcs but that the ability of Vmw110 to bind to a cellular ubiquitin-specific protease (HAUSP) is not required [16].

Regulatory relationships of USP7

  • However, USP7 does negatively regulate FOXO transcriptional activity towards endogenous promoters [17].
  • FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP [17].

Other interactions of USP7


Analytical, diagnostic and therapeutic context of USP7


  1. 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, R.D. J. Virol. (2005) [Pubmed]
  2. HAUSP/USP7 as an Epstein-Barr virus target. Holowaty, M.N., Frappier, L. Biochem. Soc. Trans. (2004) [Pubmed]
  3. 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) [Pubmed]
  4. 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, J.W., Gu, W., Cohen, R.E., Shi, Y. Cell (2002) [Pubmed]
  5. The HeLa cell protein TEF-1 binds specifically and cooperatively to two SV40 enhancer motifs of unrelated sequence. Davidson, I., Xiao, J.H., Rosales, R., Staub, A., Chambon, P. Cell (1988) [Pubmed]
  6. Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Li, M., Chen, D., Shiloh, A., Luo, J., Nikolaev, A.Y., Qin, J., Gu, W. Nature (2002) [Pubmed]
  7. GMP synthetase stimulates histone H2B deubiquitylation by the epigenetic silencer USP7. van der Knaap, J.A., Kumar, B.R., Moshkin, Y.M., Langenberg, K., Krijgsveld, J., Heck, A.J., Karch, F., Verrijzer, C.P. Mol. Cell (2005) [Pubmed]
  8. Protein interaction domains of the ubiquitin-specific protease, USP7/HAUSP. Holowaty, M.N., Sheng, Y., Nguyen, T., Arrowsmith, C., Frappier, L. J. Biol. Chem. (2003) [Pubmed]
  9. Herpes simplex virus type 1 infection induces the stabilization of p53 in a USP7- and ATM-independent manner. Boutell, C., Everett, R.D. J. Virol. (2004) [Pubmed]
  10. Molecular recognition of p53 and MDM2 by USP7/HAUSP. Sheng, Y., Saridakis, V., Sarkari, F., Duan, S., Wu, T., Arrowsmith, C.H., Frappier, L. Nat. Struct. Mol. Biol. (2006) [Pubmed]
  11. Impact of the interaction between herpes simplex virus type 1 regulatory protein ICP0 and ubiquitin-specific protease USP7 on activation of adeno-associated virus type 2 rep gene expression. Geoffroy, M.C., Chadeuf, G., Orr, A., Salvetti, A., Everett, R.D. J. Virol. (2006) [Pubmed]
  12. Transcription Enhancer Factor-1-dependent Expression of the {alpha}-Tropomyosin Gene in the Three Muscle Cell Types. Pasquet, S., Naye, F., Faucheux, C., Bronchain, O., Chesneau, A., Thi??baud, P., Th??z??, N. J. Biol. Chem. (2006) [Pubmed]
  13. Differential expression of the TEF family of transcription factors in the murine placenta and during differentiation of primary human trophoblasts in vitro. Jacquemin, P., Sapin, V., Alsat, E., Evain-Brion, D., Dollé, P., Davidson, I. Dev. Dyn. (1998) [Pubmed]
  14. Sequence analysis of the EF-1 alpha gene family of Mucor racemosus. Sundstrom, P., Lira, L.M., Choi, D., Linz, J.E., Sypherd, P.S. Nucleic Acids Res. (1987) [Pubmed]
  15. 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, M.N., Shire, K., Nguyen, T., Zhang, R.G., Liao, J., Lee, W., Edwards, A.M., Arrowsmith, C.H., Frappier, L. Mol. Cell (2005) [Pubmed]
  16. Herpes simplex virus type 1 immediate-early protein vmw110 induces the proteasome-dependent degradation of the catalytic subunit of DNA-dependent protein kinase. Parkinson, J., Lees-Miller, S.P., Everett, R.D. J. Virol. (1999) [Pubmed]
  17. FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP. van der Horst, A., de Vries-Smits, A.M., Brenkman, A.B., van Triest, M.H., van den Broek, N., Colland, F., Maurice, M.M., Burgering, B.M. Nat. Cell Biol. (2006) [Pubmed]
  18. A diverse family of proteins containing tumor necrosis factor receptor-associated factor domains. Zapata, J.M., Pawlowski, K., Haas, E., Ware, C.F., Godzik, A., Reed, J.C. J. Biol. Chem. (2001) [Pubmed]
  19. Assignment1 of herpesvirus-associated ubiquitin-specific protease gene HAUSP to human chromosome band 16p13.3 by in situ hybridization. Robinson, P.A., Lomonte, P., Leek, n.u.l.l., Markham, A.F., Everett, R.D. Cytogenet. Cell Genet. (1998) [Pubmed]
  20. p53 apoptotic pathway molecules are frequently and simultaneously altered in nonsmall cell lung carcinoma. Mori, S., Ito, G., Usami, N., Yoshioka, H., Ueda, Y., Kodama, Y., Takahashi, M., Fong, K.M., Shimokata, K., Sekido, Y. Cancer (2004) [Pubmed]
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