DUBs antagonize the activities of ubiquitin ligases. Although the function of most human DUBs remains to be determined, it has become clear that DUB activities are indispensible for the normal functions of ubiquitin-proteasome pathways. Abnormal cellular expression of DUBs or the loss of function due to mutation in certain DUB genes have been linked to various human diseases. Among the five subfamilies (see the accompanying figure), USPs are emerging as promising targets for pharmacological intervention because of their connection to many human diseases.
The activity of DUBs, in particular USPs, is stringently regulated through their interaction with many other protein partners. A recent global proteomic analysis of human DUBs identified 774 interacting proteins for the 75 DUBs studied. Remarkably, a number of human USPs were found to be associated with WD40-repeat proteins that adopt a beta-propeller structure. Given its widespread occurrence, the interaction between WD40-repeat proteins and USPs likely represents a fundamentally important way of regulating USP activity. We are investigating the catalysis and regulation of DUBs that function in DNA damage response and cell cycle control. We are also engaged in identifying and developing DUB inhibitors through high-throughput screening (HTS) and chemical synthesis.
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