Aneuploidy affects DNA metabolism and segregation to cause genomic instability

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DESCRIPTION (provided by applicant): The work described within this proposal intends to address the hypothesis that aneuploidy promotes genomic instability through affecting DNA metabolism and/or chromosome segregation. We propose to use aneuploid yeast strains, which all exhibit various forms of genomic instability, to determine which aspects of cellular physiology contribute to this phenotype. Defects in DNA metabolism, including replication and repair, as well as defects in the chromosome segregation machinery can negatively impact genomic stability. Thus, if aneuploidy itself is sufficient to cause genomic instability, it is crucial to determine the exact processes affected, and the specific aims of the proposal address prime targets. Since genomic alteration and the subsequent accumulation of mutations drive the formation of tumors, if aneuploidy is sufficient to cause genomic instability through the processes we plan to investigate, it would shed new light into aneuploidy's role in tumorigenesis and also open the door for potential new therapeutic agents that might specifically target processes preferentially affected in aneuploid cells. PUBLIC HEALTH RELEVANCE: The research proposed here seeks to gain insight into the role that aneuploidy plays in human disease, specifically cancer. Aneuploidy is strongly correlated with cancer, though its role remains unclear. Determining the effects of aneuploidy cellular physiology, particularly its effect on genomic stability, will not only help determine a possible cause of cancer but also provide a target for new therapeutic agents.