Regulation of Chromosome Segregation

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Accurate cell division depends upon proper chromosome segregation into daughter cells. Defects in chromosome segregation lead to genetic instability and aneuploidy, hallmarkers of cancer and birth defects. Chromosomes segregate using their kinetochores, the specialized protein structures that are assembled on centromeric DNA sequences and mediate attachment to the mitotic spindle. Although many kinetochore components have been identified, it is unknown how kinetochores are regulated to mediate chromosome segregation. The long-term goal of this project is to elucidate the regulation and mechanisms of kinetochore function and chromosome segregation using the budding yeast Saccharomyces cerevisiae is a model system. A key regulator of kinetochore function is the conserved Ip11/aurora2 protein kinase. Since defects on the yeast Ip11p kinase lead to aneuploidy and the human aurora2 kinase is an oncogene, studies on the kinase are important to understanding both chromosome segregation and cellular transformation. This proposal This proposal focuses on the Ip11/aurora2 kinase and another conserved kinetochore component, the histone H3 variant Cse4p, as a means toward elucidating the mechanisms of chromosome segregation. The specific aims include: 1) analyzing Ip11p and Cse4p assembly into kinetochores to gain insight into mechanisms of kinetochore assembly, 2) investigating the regulation and substrates of the Ip11p kinase to understand how it regulates chromosome segregation, 3) examining the role of Ip11p in the spindle checkpoint, and 4) investigating the kinetochore functions of the Ip11p and Cse4p proteins to understand how kinetochores are regulated. These studies will lead to a better understanding of the mechanisms of chromosome segregation and the role of the Ip11/aurora2 kinase in genomic stability, studies may elucidate details about the generation of cancer and provide new avenues for therapy.