Microtubule Dynamics and Chromosome Segregation

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Project Summary The broad goal of this project is to understand the mechanistic contribution of force generation by kinesin-related motors and dynamic microtubules to chromosome segregation. Both microtubules and motors represent excellent targets for anti-cancer drugs but to make wise choices for developing therapeutics it is necessary to understand their contribution to cell division in detail. We have identified two relatively unstudied kinesin-related motors, Kif25 and Kif9 that contribute key activities to facilitate proper mitotic spindle function. We will use high resolution live cell imaging, gene editing, Rapamycin-dependent knock-sideways approaches and single molecule assays in vitro to investigate how Kif25 suppresses premature centrosome separation and how it exerts inward force on the mitotic spindle sufficient to activate the spindle assembly checkpoint. We will use similar techniques to understand how Kif9 enables dividing cells to bypass the spindle assembly checkpoint. Underlying these activities are the dynamic microtubules that serve as substrates for kinesin activity. We have developed a number of assays that allow us to quantify subtle changes in microtubule dynamics. Stable alterations in microtubule assembly dynamics are often result from loss or overexpression of kinesin-like modulators, or other drivers of tumorigenesis. We will use cell-based assays and live imaging to determine the mechanism by which altered microtubule assembly rates impact long-term chromosome instability.