Examining cell division mechanisms using chemical biology
Tarun Kapoor, Rockefeller University
We take a multidisciplinary approach to determine the molecular and physical basis for how during cell division exactly one copy of our genome is delivered to each daughter cell. Errors in this process are associated with developmental defects and diseases in humans. Central to our approach in addressing long-standing questions relating to cell division is the use of cell-permeable chemical inhibitors, including those we have discovered, designed, or validated as probes. The temporal control over protein function that can be achieved through chemical inhibition is particularly suited to the study of cell division, a process that takes minutes, with several steps occurring within seconds. By combining the use of small molecule probes with state-of-the-art microscopy to examine the dynamics of cell division, we match as closely as possible, the time-scale of observations to that of systematic perturbations. I will discuss our analysis of: (i) How proper chromosome-spindle attachments are established during cell division, (ii) How microtubule self-organization results in the formation of bipolar metaphase spindles. Single molecule studies with purified components and live cell analysis of protein and phosphorylation dynamics will be highlighted. Chemical inhibitors of motor proteins (e.g. kinesi-5) and kinases (Aurora and Polo-like kinases), involved in the two processes I discuss, are currently in clinical trials as anti-cancer agents. Our work impacts the further development of these inhibitors by providing insight into the functions of the target proteins, and by revealing consequences of specifically inhibiting their activities in human cancer cells.
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