Investigating the Cell Division Machinery

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SUMMARY Cell division is a complex and specifically orchestrated set of events that culminates in the equal segregation of sister chromatids into two cells. It relies on a multitude of protein complexes, protein-protein interactions, and regulatory mechanisms driven by the activities of posttranslational modification enzymes. Misregulation of cell division can lead to unrestricted or defective cell divisions that can promote chromosomal instability and aneuploidy, which are associated with many types of cancers. Through proteomic and genetic screens we have uncovered novel proteins that are critical to the fidelity of cell division. We have applied multidisciplinary approaches that utilize cell biology, molecular biology, computational biology and biochemistry to analyze the function of these proteins. These approaches have allowed us to define the function of many new proteins with critical roles in key cell division events including centrosome homeostasis, mitotic microtubule spindle assembly, spindle assembly checkpoint function and cytokinesis. Furthermore, we have applied chemical biology approaches to define novel cell division inhibitors and their mechanisms of action, which we have used as molecular probes for dissecting the mechansims of cell division and for the development of cancer therapeutics. In this proposal, we propose to advance our understanding of the repertoire of proteins and their mechanisms that are important to cell division. This will include functional analysis of novel and poorly- characterized microtubule-associated proteins involved in centrosome homeostasis and mitotic spindle assembly, and novel components that contribute to the fidelity of the spindle assembly checkpoint. Overall, the proposed research studies will increase our understanding of the repertoire of cell division enzymes, their function whithin critical cell division events, how they are regulated, and how they coordinate with each other to ensure proper cell division. These studies will also advance our understanding of the cell division mechanisms that are dysregulated in human developmental and proliferative diseases.