Molecular basis for motor-cargo cooperation in mitosis

Defects in chromosome segregation give rise to aneuploidy and chromosome instability, important hallmarks of cancer. Equal partitioning of sister chromatids to daughter cells requires microtubules to assemble into a mitotic spindle and to power chromosome segregation. Microtubules depend on multiple microtubule motor proteins to assemble into a spindle and segregate chromosomes. However, how motors cooperate with each other and with their cargos to drive mitosis is still virtually unknown. I will use a holistic mechanistic approach to understand how motor cooperation ensures faithful mitosis. We will focus on two key mitotic motor families, the non-motile Kinesin-13 microtubule depolymerases and CENP-E, critical for chromosome alignment, as paradigms for understanding motor cooperation during cell division. Combining structural and cell biology with single molecule reconstitution, we will define how Kinesin-13 motors cooperate with Kinesin-8 translocating motors for microtubule end targeting and depolymerization, and how CENP-E cooperates with the outer kinetochore of unaligned chromosomes, to achieve chromosome biorientation and segregation. These studies will provide a mechanistic understanding of the emerging role of kinesin-cargo cooperation in ensuring faithful cell division. Understanding these interactions will create new opportunities for the rational design of kinesin inhibitors in the treatment of cancer.