Grant: Operating Grant

The task which each eukaryotic cell has to accomplish dictates the levels of enzymes and proteins it produces at any given stage of its live cycle. This equilibrium of protein expression and degradation is in part regulated by a process called ubiquitination. During this process the small protein ubiquitin is attached to other proteins in the cell which determines their intracellular fate. Ubiquitination plays important roles in controlling protein degradation, protein localization and cellular signalling. Deubiquitination counteracts the effects initiated by ubiquitination and by that regulates and modulates these effects. The human genome encodes approximately 100 deubiquitinating enzymes (DUBs); each DUB deubiquitinates a specific set of proteins and thereby modulates specific biological functions. Because Dubs are enzymes with well-defined catalytic sites, they have attracted considerable attention as therapeutic targets for cancer treatment. As has been the case with kinase inhibitors, specific inhibitors of Dubs would be invaluable tools for understanding normal and cancer biology and they could be developed into anti-cancer drugs. Our overall goal is to break new ground to generate the first-ever specific inhibitors of enzymes in the deubiquitination pathway. These inhibitors will be used as tools to probe biology and for the validation of Dubs as potential targets for cancer therapeutics. Furthermore, structural analyses will elucidate the roles of critical contacts that mediate specificity and affinity, and this information will aid the design of small molecule inhibitors. Importantly, the general strategy will be extendable beyond the USP family to other DUBs, and also, to enzymes involved in the ubiquitination pathway. The tools and knowledge acquired through our research will greatly enhance our understanding of deubiquitination and will drive many additional experiments that may eventually lead to novel therapeutics for unmet medical needs.