Maintaining a stable genome is essential for normal cell growth, and increased genome instability is a well-documented property of cancer cells. Inherited cancer susceptibility syndromes are known that are due to defects in DNA repair and/or DNA damage responses resulting in increased spontaneous or DNA damage-induced genome instability. However, while increased genome instability in cancer cells is well documented, less is known about the actual mechanisms by which genome rearrangements arise or what pathways prevent genome instability. Understanding the mechanisms of genome instability and the pathways that suppress in will impact on human health for several reasons: 1) The identification of genes that function in suppressing genome instability may provide insights into the types of defects that give rise to genome instability in cancers; and 2) Many chemotherapeutic agents damage DNA and understanding how damage interacts with pathways that suppress genome instability could lead to improvements in the efficacy of these agents. The goal of this proposal is to use Saccharomyces cerevisiae to identify the pathways that function in suppressing genome instability. Related goals are to understand the types of metabolic errors and mechanisms that give rise to genome instability and to provide insights into the types of defects that cause genome instability in cancer cells. Previously a new approach was developed for identifying pathways and genes that suppress genome instability. The following lines of experimentation will now be carried out: 1) A broader array of methods for studying genome instability will be developed; 2) Genetic studies of genes that suppress genome instability will be performed to better define the recombination, checkpoint and telomere maintenance pathways that suppress genome instability; 3) Genetic screens will identify additional genes which when mutated or overexpressed cause increased genome instability; 4) Break-induced replication, a recombination pathway that functions in suppression of genome instability, will be reconstituted in vitro; 5) A limited number of biochemical studies of the MER3 and MSH4-MSH5 proteins will be completed; and 6) mouse and human homologues of the S. cerevisiae genome instability genes will be identified to extend the study of genome instability to mouse and human systems. The ultimate goal of these studies will be to provide a comprehensive picture of the pathways and mechanisms that suppress genome instability.
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