Microtubules are unstable filaments that grow and shrink by subunit addition and loss. During mitosis, microtubules organize into a bilaterally symmetric apparatus termed the mitotic spindle which acts to segregate replicated chromosomes into two equal sets. Chemotherapeutic agents that interfere with mitotic spindle function are effective at eradicating cancer cells. Better understanding of the cell division process is likely to identify additional drug targets that are useful in cancer disease management. Chromosomes engage microtubules in the mitotic spindle through specialized structures called kinetochores. Growth and shortening of kinetochore-microtubules generate forces that power chromosome movement. Kinetochore-microtubule dynamics must be modulated to produce coordinated sister kinetochore movements, but little is known about the underlying mechanisms. In this grant, we will investigate the biochemical mechanism by which a kinetochore-localized motor protein affects microtubule polymerization dynamics. We will also address how one master regulator of mitosis, Polo like kinase 1, uses spindle forces as a cue to dictate chromosome movements. Our work will advance our knowledge of cell division mechanisms, and have immediate relevance to ongoing studies exploring the suitability of Polo kinases as cancer drug targets.
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