Molecular basis for motor-cargo cooperation in mitosis (360G-Wellcome-207430_Z_17_Z)

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.