Because fundamental aspects of mitosis are clearly conserved in eukaryotic organisms, studies in model experimental systems are highly relevant to understanding mitotic chromosome distribution in human beings. Chromosomal aneuploidies in man are associated with prevalent disease states including malignant tumor formation, birth defects, and prenatal inviability. An understanding of the processes that normally control the transmission of euploid chromosome sets and the ordered progression of cell cycle events in eukaryotes will be essential to characterization of the defects leading to aneuploidy associated disease, with important consequences for the development of prediction and prevention measures. The distribution of a euploid chromosome set to each daughter nucleus of a mitotic division requires the execution of temporally ordered processes controlling the replication, organization, and segregation of the chromosomal DNA with its associated proteins. The fidelity of chromosome transmission depends upon the interaction of chromosomal elements (such as centromeres, origins of replication, and telomeres) with the extrachromosomal structures that participate in the complex series of ordered processes that culminate in cell division. We have recently described mitotic delays induced by the presence of mutations in kinetochore proteins or centromeric DNA in the budding yeast S. cerevisiae. Preliminary studies indicate that these delays reveal the existence of surveillance mechanism(s) monitoring kinetochore state and controlling the timing of cell cycle progression through mitosis to ensure high levels of chromosome transmission fidelity. This hypothesis will be tested in yeast using a variety of existing molecular and genetic tools, and taking advantage of mutations in centromere DNA, kinetochore protein mutants, and candidate surveillance mutants. Proteins essential for the mitotic delay(s) will be identified through the study of mutants that fail to delay in the presence of abnormal kinetochores. Further analysis of the mutants will test whether their primary defect is in the timing of chromosome segregation, and whether their normal role is extrinsic to segregation functions of the kinetochore. Detailed characterization of the delays induced by centromere DNA mutations and by kinetochore protein mutants will identify late-occurring steps in the cell cycle. Genetic interaction studies will define the number of delay phenomena under study, and will reveal the relationships between the surveillance functions disrupted in delay-deficient mutants. This work draws on the strength of budding yeast as a model eukaryote, and will form the foundation for future research in other systems on conserved processes ensuring high fidelity chromosome segregation in mitosis.
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