Progress on our specific aims over the past four years has led to our discovery of a novel and conserved class of ubiquitin E3 ligases that targets a subunit of the microtubule-severing complex called katanin for ubiquitin-mediated proteolytic degradation, shortly after the completion of meiosis. Katanin is required for meiosis;its subsequent degradation is required for the proper assembly of mitotic spindles, and for the regulation of cortical microfilament contractility during cytokinesis. Thus in addition to influencing regulators of cell cycle progression, we have shown that ubiquitin-mediated proteolysis also influences the cell division machinery itself. Importantly, the E3 ligase we discovered is the founding member of a new class of Cullin- based E3 ligases, composed of a Cullin3 scaffold and one of a large and conserved family of novel adaptor proteins. This finding greatly extends our understanding of the full range of ubiquitin E3 target specificity, and we also have provided new insights into the regulation of E3 ligases. Finally, from extensive screens for conditional mutants with cell division defects, we have identified (i) a chromokinesin, and three additional mutants, that influence central spindle assembly or stability, and the completion of cytokinesis, and (ii) a large collection of meiosis-defective mutants. Our new aims seek to improve our understanding of cytokinesis and meiosis through a molecular genetic investigation of these new mutants. We also will continue our efforts to identify factors that influence E3 ligase function and katanin degradation, in an ongoing collaboration with Dr. Matthias Peter at the ETH in Zurich, Switzerland. The processes and genes we propose to investigate are relevant to important human diseases, including cancer and neurodegenerative disease.
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