Increased genome instability is characteristic of many cancers. Inherited cancer susceptibility syndromes have been identified that are associated with increased spontaneous or DNA damage-induced genome instability in both normal tissues and, ultimately, the cancers that arise. Genome rearrangements have been documented that result in mutations that drive the development of cancer or result in loss of heterozygosity events that uncover recessive mutations in tumor suppressor genes. In addition, there are many examples of genome rearrangements that are the mutations that underlie different genetic diseases. However, while genome instability is well documented, and is being intensely studied, our knowledge of the actual mechanisms by which genome rearrangements arise or what pathways prevent genome instability remains limited. Understanding the mechanisms of genome instability and the pathways that suppress it will impact on human health for several reasons: 1) Many chemotherapeutic agents damage DNA and understanding how damage interacts with the pathways that suppress genome instability could lead to improvements in the efficacy of these agents;2) The identification of genes that function in suppressing genome instability may provide insights into the types of defects that cause genome instability in cancers;and 3) The identification of genes that suppress genome instability will provide new candidate tumor suppressor genes for investigation and candidate genes in which polymorphisms may show interactions with environmental agents. The main goal of this proposal is to identify the genes and pathways that function in suppressing genome instability using Saccharomyces cerevisiae as a model system. Related goals are to understand the types of metabolic errors and mechanisms that cause genome instability and provide insights into the defects that might cause genome instability in cancer cells. The proposed work is based on insights obtained using a previously developed quantitative genetic assay for genome instability. The following lines of experimentation will now be carried out: 1) Methods for studying genome instability will continue to be developed and refined;2) Systematic genetic screens will be performed to identify the genes and pathways that suppress genome instability;3) Mechanistic studies will be performed to elucidate key features of the pathways that suppress genome instability and to identify the aberrant DNA molecules that give rise to genome rearrangements;4) The biochemical properties .of mutant Rpa proteins and the interaction between PCNA and different proteins that act in the suppression of genome instability will be studied;5) Prpteomic and coupled genetic approaches will be used to study the checkpoint proteins thought to function in the suppression of genome instability;and 6) mouse and human hornologues of the S. cerevisiae genome instability genes will be identified to extend the study of genome instability to mouse and, ultimately, 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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