The generation, survival and development of all organisms depend on the faithful execution of cell division. A key event in the cell cycle is the precise partitioning of every pair of duplicated chromosomes to daughter cells.  Defects in segregation lead to aneuploidy, the state where entire chromosomes are gained or lost.  Aneuploidy is a hallmark of most tumor cells and has been postulated to be a major factor in the evolution of cancer.  It is also the leading cause of spontaneous miscarriages and hereditary birth defects in humans.  Our goal is to understand the mechanisms that ensure accurate chromosome segregation and thus maintain genomic stability and prevent human disease.  This work is critical not only for elucidating fundamental aspects of this essential biological process, but is also required for the design of better therapeutic interventions in the long-term.

Chromosome segregation is directed by the kinetochore, the macromolecular protein structure that assembles onto centromeric chromatin. The kinetochore binds to the microtubules that compose the mitotic spindle and physically pulls chromosomes into daughter cells. If there are defects in kinetochore-microtubule attachments or the tension generated by microtubule pulling forces, the spindle checkpoint halts the cell cycle. It is essential that every chromosome assemble a single kinetochore on centromeric chromatin during every cell cycle. Our lab is taking a comprehensive approach to understanding the assembly, functions and architecture of the kinetochore and the underlying specialized centromeric chromatin. We have developed techniques to purify native kinetochore particles from yeast and human cells and to assemble kinetochores de novo. We are now exploring the following key questions using budding yeast and human cells.

• How does tension promote accurate chromosome segregation?
• What is the high resolution structure of the macromolecular kinetochore complex?
• How do kinetochores assemble and what are the key regulatory steps?
• How is the spindle checkpoint activated and silenced by tension and attachment at kinetochores?
• How is the underlying specialized chromatin assembled and maintained exclusively at the centromere on each chromosome?
• How does RNA contribute to centromere and kinetochore identity and function?
• How are kinetochore-microtubule attachments made and regulated?
• How do cells detect and correct errors in kinetochore-microtubule attachments?
• How do kinetochore cluster in vivo and what is the function of kinetochore clustering?