Research Focus

The attachment of ubiquitin to target proteins plays important regulatory tasks in eukaryotic cellular processes. The most studied after effect of ubiquitination is the subsequent degradation of the target protein by the 26S proteasome. Degradation of cellular proteins has many regulatory effects including cell cycle progression, stress response, signal transduction, transcriptional activation and DNA repair. Protein ubiquitination is both dynamic and reversible. The ubiquitination of target proteins can be reversed by the action of deubiquitinating enzymes. Deubiquitinating enzymes play important roles in the salvage of proteins from destruction by the 26S proteasome. Since this is a relatively new topic of research, the biochemistry and role of the enzymes involved in deubiquitination is not well understood. A crucial piece of information lacking about USPs is the identification of their target proteins. It will allow a more complete picture of the ubiquitination/deubiquitination pathways and the biological processes that they govern to be drawn. Also missing however is functional data resulting from the removal of these proteins from the cell.

One class of deubiquitinating enzymes are known as ubiquitin specific proteases (USPs). USPs are presumed to be involved in the removal of ubiquitin molecules from specific target proteins. There are several examples in the literature that demonstrate the importance of USPs in cellular functions. However, the most notable is USP7-p53-mdm2. USP7 is able to regulate the levels of p53 and mdm2 proteins by deubiquitinating these proteins once they have been targeted for degradation by ubiquitination.

Representative publications:

Pfoh R , Lacdao IK , Georges AA , Capar A , Zheng H , Frappier L , Saridakis V. (2015). Crystal Structure of USP7 Ubiquitin-like Domains with an ICP0 Peptide Reveals a Novel Mechanism Used by Viral and Cellular Proteins to Target USP7.PLoS Pathogens. 11(6): e1004950.
Pfoh R , Lacdao IK , Saridakis V. (2015). Deubiquitinases and the new therapeutic opportunities offered to cancer. Endocrine-related cancer. 22(1): T35-54.

Jagannathan M , Nguyen T , Gallo D , Luthra N , Brown GW , Saridakis V , Frappier L. (2014). A role for USP7 in DNA replication. Molecular and cellular biology. 34(1): 132-45.

Sarkari F , Wheaton K , La Delfa A , Mohamed M , Shaikh F , Khatun R , Arrowsmith CH , Frappier L , Saridakis V , Sheng Y. (2013). Ubiquitin-specific protease 7 is a regulator of ubiquitin-conjugating enzyme UbE2E1. The Journal of Biological Chemistry. 288(23)

Shloush J , Vlassov JE , Engson I , Duan S , Saridakis V , Dhe-Paganon S , Raught B , Sheng Y ,Arrowsmith CH. (2011). Structural and functional comparison of the RING domains of two p53 E3 ligases, Mdm2 and Pirh2. The Journal of Biological Chemistry. 286(6)

Sarkari F , La Delfa A , Arrowsmith CH , Frappier L , Sheng Y , Saridakis V. (2010). Further insight into substrate recognition by USP7: structural and biochemical analysis of the HdmX and Hdm2 interactions with USP7. Journal of Molecular Biology. 402(5)

Research Areas