Aneuploidy is a nearly ubiquitous feature of human cancers. Investigation of the molecular mechanisms of chromosome instability is important for the development of effective strategies for cancer prevention and therapy. The long-term objective of this project is to determine the mechanisms by which genetic and environmental factors affect the fidelity of chromosome segregation. The basic hypotheses of this proposal are that: 1) certain mutations in genes encoding DNA polymerases can cause increased chromosome loss and nondisjunction by disrupting coordination of DNA synthesis and chromosome segregation, and 2) chromosome instability in such mutants can be further increased by exposure to environmental genotoxicants. These hypotheses will be tested by pursuing the following specific aims: (1) develop a novel system for quantitative analysis of chromosome missegregation in yeast that allows direct selection for nondisjunction events, (2) identify mutations in genes encoding DNA polymerases that would lead to increase in spontaneous or environmental genotoxicant-induced chromosome missegregation, and (3) investigate the mechanisms of chromosome segregation defects in mutants identified in aim 2. The effects of UV-irradiation, alkylating agents, oxidative stress and the radiomimetic chemical bleomycin on chromosome stability will be tested. These studies will provide the basis for identification of human genes and environmental factors involved in induction of aneuploidy in human cancer cells.
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