Research Projects


Our long-term goal is to understand the mechanisms that ensure the fidelity of chromosome segregation and how perturbations in these processes contribute to human diseases such as cancer. Chromosome segregation requires the action of at least two major molecular machines: the kinetochore and the anaphase spindle. The kinetochore is a multi-protein complex built on centromeric DNA and attaches chromosomes to the mitotic spindle. The anaphase spindle also consists of large number of proteins that mediate spindle elongation and the full resolution of sister chromatids in anaphase before cell division is completed. We are focused on three main questions related to these complex processes:

  1. What are the molecular mechanisms that ensure proper kinetochore assembly? We are interested in how the Hsp90 chaperone machinery ensures the efficient assembly of kinetochores and how its connection to protein degradation pathways acts as a quality control system to ensure accurate assembly. We are also interested in how Hsp90-chaperones contribute to the “plasticity” of kinetochore complexes, allowing them to adapt under cell stress or to serve distinct roles at different stages of the cell cycle. Our focus is on kinetochores but these principles are likely to apply to a wide range of multi-protein complexes. 
  2. How are the events of chromosome segregation, sister chromatid resolution and cytokinesis coordinated during anaphase? To address this question, we study a group of proteins called chromosome passengers that include the Aurora B kinase. We are focused on understanding how Aurora B is regulated during anaphase to coordinate the resolution of conjoined sister chromatids (i.e., chromosome bridges) with the cell division machinery. 
  3. How do cancer cells develop aneuploidy and how does this process contribute to disease onset and progression? To address these important issues, we have focused on colorectal cancer. Tumor cells from patients exhibit a high rate of chromosome instability and our studies have demonstrated that a dominant gain of function from canonical mutations in the adenamotous polyposis coli (APC) can perturb mitotic spindle function and lead to increased tetraploid cells. We are currently exploring the impact of these changes on pre-cancer cells using mouse cancer and cell culture models. © K.B. Kaplan 2012