Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

USP7 (Ubiquitin-Specific Protease 7)

  • Bhaskar Basu
  • Seemana Bhattacharya
  • Gouranga Saha
  • Mrinal K. GhoshEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101812



Historical Background

Proteins are vital to the structure and functioning of cells, and so the regulated turnover of proteins is an absolute essential of cellular metabolism. This necessity for the major part has been found to be taken care of by the ubiquitin-proteasome system (UPS). The system was discovered as a result of the work carried out by Avram Hershko, Aaron Ciechanover, and Irwin Rose, for which they shared the 2004 Nobel Prize in Chemistry. The UPS in its most simplified form consists of a tagging factor in the form of the small protein ubiquitin, enzymes that mediate the tagging of unwanted or damaged proteins, and the proteasome, a large molecular shredder that cleaves tagged proteins in to smaller peptides for use in other anabolic processes. More than 80% of all cellular proteins undergo degradation by the UPS, highlighting its importance in regulating various eukaryotic cellular processes such as cell cycle progression, stress response,...

This is a preview of subscription content, log in to check access.



Financially supported by grants from CSIR, India (EMPOWER-OLP-002, MEDCHEM-BSC0108 & CSIR-MAYO: MLP-0017), and DST Nano Mission program (SR/NM/NS-1058/2015) to Dr. Mrinal K Ghosh.

Conflict of Interest The authors declare no conflict of interest.


  1. Bhattacharya S, Ghosh MK. Cell death and deubiquitinases: perspectives in cancer. BioMed Res Int. 2014a. Article ID 435197.Google Scholar
  2. Bhattacharya S, Ghosh MK. HAUSP, a novel deubiquitinase for Rb – MDM2 the critical regulator. FEBS J. 2014b;281:3061–78.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Boutell C, Canning M, Orr A, Everett RD. Reciprocal activities between herpes simplex virus type 1 regulatory protein ICP0, a ubiquitin E3 ligase, and ubiquitin-specific protease USP7. J Virol. 2005;79:12342–54.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Canning M, Boutell C, Parkinson J, Everett RD. A RING finger ubiquitin ligase is protected from autocatalyzed ubiquitination and degradation by binding to ubiquitin-specific protease USP7. J Biol Chem. 2004;279: 38160–8.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Collaran A, Collins PE, O’Carroll C, Ahmed A, Mao X, McManus B, Kiely PA, Burstein E, Carmody RJ. Deubiquitination of NF-κB by ubiquitin-specific protease-7 promotes transcription. PNAS. 2013;110:618–23.CrossRefGoogle Scholar
  6. Cummins JM, Rago C, Kohli M, Kinzler KW, Lengauer C, Vogelstein B. Tumour suppression: disruption of HAUSP gene stabilizes p53. Nature. 2004;428:1 p following 486.PubMedPubMedCentralCrossRefGoogle Scholar
  7. D’Arcy P, Wang X, Linder S. Deubiquitinase inhibition as a cancer therapeutic strategy. Pharmacol Ther. 2015;147:32–54.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Daubeuf S, Singh D, Tan Y, Liu H, Federoff HJ, et al. HSV ICP0 recruits USP7 to modulate TLR-mediated innate response. Blood. 2009;113:3264–75.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 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;16:1519–30.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Higa M, Zhang X, Tanaka K, Saijo M. Stabilization of ultraviolet (UV)-stimulated Scaffold protein A by Interaction with ubiquitin-specific peptidase 7 is essential for transcription-coupled nucleotide excision repair. J Biol Chem. 2016;291:13771–9.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Hu M, Li P, Li M, Li W, Yao T, Wu J-W, Gu W, Cohen RE, Shi Y. Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde. Cell. 2002;111:1041–54.Google Scholar
  12. Hu H-J, Zhang L-G, Wang Z-H, Guo X-X. FoxO6 inhibits cell proliferation in lung carcinoma through up-regulation of USP7. Mol Med Rep. 2015;12:575–80.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Khoronenkova SV, Dianova II, Ternette N, Kessler BM, Parsons JL, Dianov GL. ATM-dependent downregulation of USP7/HAUSP by PPM1G activates p53 pesponse to DNA damage. Mol Cell. 2012;45:801–13.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Lecona E, Rodriguez-Acebes S, Specks J, Lopez-Contreras AJ, Ruppen I, Murga M, Muñoz J, Mendez J, Fernandez-Capetillo O. USP7 is a SUMO deubiquitinase essential for DNA replication. Nat Struct Mol Biol. 2016;23:270–7.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J, Gu W. Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature. 2002;416:648–53.PubMedCrossRefGoogle Scholar
  16. Li M, Brooks CL, Kon N, Gu W. A dynamic role of HAUSP in the p53-Mdm2 pathway. Mol Cell. 2004;13:879–86.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Meulmeester E, Maurice MM, Boutell C, Teunisse AFAS, Ovaa H, Abraham TE, Dirks RW, Jochemsen AG. Loss of HAUSP-mediated deubiquitination contributes to DNA damage-induced destabilization of Hdmx and Hdm2. Mol Cell. 2005;18:565–76.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Mungamuri SK, Qiao RF, Yao S, Manfredi JJ, Gu W, Aaronson SA. USP7 enforces heterochromatinization of p53 target promoters by protecting SUV39H1 from MDM2-mediated degradation. Cell Rep. 2016;14:2528–37.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Song MS, Salmena L, Carracedo A, Egia A, Lo-Coco F, Teruya-Feldstein J, Pandolfi PP. The deubiquitinylation and localization of PTEN are regulated by a HAUSP–PML network. Nature. 2008;455:813–7.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Tavana O, Li D, Dai C, Lopez G, Banerjee D, Kon N, Chen C, Califano A, Yamashiro DJ, Sun H, et al. HAUSP deubiquitinates and stabilizes N-Myc in neuroblastoma. Nat Med. 2016;22:1180–6.PubMedPubMedCentralCrossRefGoogle Scholar
  21. van der Knaap JA, Kumar BRP, Moshkin YM, Langenberg K, Krijgsveld J, Heck AJR, Karch F, Verrijzer CP. GMP synthetase stimulates histone H2B deubiquitylation by the epigenetic silencer USP7. Mol Cell. 2005;17:695–707.PubMedCrossRefGoogle Scholar
  22. Vugmeyster Y, Borodovsky A, Maurice MM, Maehr R, Furman MH, Ploegh HL. The ubiquitin–proteasome pathway in thymocyte apoptosis: caspase-dependent processing of the deubiquitinating enzyme USP7 (HAUSP). Mol Immunol. 2002;39:431–41.PubMedCrossRefGoogle Scholar
  23. Wang Q, Ma S, Song N, Li X, Liu L, Yang S, Ding X, Shan L, Zhou X, Su D, et al. Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis. J Clin Invest. 2016;126:2205–20.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Wu H-T, Kuo Y-C, Hung J-J, Huang C-H, Chen W-Y, Chou T-Y, Chen Y, Chen Y-J, Chen Y-J, Cheng W-C, et al. K63-polyubiquitinated HAUSP deubiquitinates HIF-1α and dictates H3K56 acetylation promoting hypoxia-induced tumour progression. Nat Commun. 2016;7:13644.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Zhou Z, Yao X, Li S, Xiong Y, Dong X, Zhao Y, Jiang J, Zhang Q. Deubiquitination of Ci/Gli by Usp7/HAUSP regulates Hedgehog signaling. Dev Cell. 2015;34:58–72.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Zhu L, Liu R, Zhang W, Qian S, Wang J-H. MicroRNA-205 regulates ubiquitin specific peptidase 7 protein expression in hepatocellular carcinoma cells. Mol Med Rep. 2015;12:4652–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Bhaskar Basu
    • 1
  • Seemana Bhattacharya
    • 2
  • Gouranga Saha
    • 1
  • Mrinal K. Ghosh
    • 1
    Email author
  1. 1.Cancer Biology and Inflammatory Disorder DivisionCouncil of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB)KolkataIndia
  2. 2.Department of Leukemia (T6. 3948/T6.3986)UT MD Anderson Cancer CenterHoustonUSA