Abstract: Precise regulation of mitosis is critical so that the resulting daughter cells have exactly one copy of each chromosome, since mis-segregation of chromosomes is implicated in the formation of birth defects and in the initiation and progression of cancer. Kinetochores — large protein structures assembled upon centromeric chromatin — serve as key orchestrators of mitosis.
These structures connect chromosomes to spindle microtubules through the NDC80 complex, the “core” kinetochore-microtubule attachment factor. Controlled changes in kinetochore-microtubule attachment stability allow for correction of erroneous attachments in early mitosis, and force generation for chromosome movements in late mitosis. Importantly, the status of kinetochore-microtubule attachment is continually relayed to the spindle assembly checkpoint so that mitosis is arrested if kinetochores are not stably attached to microtubules, and a mitotic exit program is initiated when stable attachment is achieved.
Using a combination of cell biological approaches, in vitro biochemical reconstitution, and mathematical modeling, our lab is currently investigating how kinetochore-microtubule attachments are regulated and monitored during mitosis to ensure accurate chromosome segregation.