Genetic control of mitotic spindle assembly and function

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DESCRIPTION (provided by applicant): The long-term goals of this project are to understand how the function of the mitotic spindle is integrated into the cell cycle in the budding yeast Saccharomyces cerevisiae. The spindle checkpoint is an evolutionarily conserved mitotic regulatory system that arrests cells when chromosomes are not properly aligned on the mitotic spindle apparatus. Mutations in spindle checkpoint genes have been implicated in genomic instability and tumor progression in humans. Various ant-tumor chemotherapeutic agents, like taxol, cause human cells to arrest in mitosis by activating the spindle checkpoint. We will use a combination of genetic approaches to determine the role that a single chromosome domain, the kinetochore, plays in the spindle checkpoint. We will also determine if a single chromosome is capable of activating the spindle checkpoint and we will determine the role that tension plays in the activation process. We will use a synthetic lethal screen with to explore the complexity that exists within the spindle checkpoint pathways. Our experiments will identify some of the important regulatory mechanisms that control genomic stability in a variety of cell types. The spindle checkpoint genes may identify molecular targets for chemotherapeutic intervention in some cancers and birth defects.