Mechanism of break-induced replication in yeast

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DESCRIPTION (provided by applicant): There is a gap in understanding what causes genomic rearrangements that lead to cancer. It was recently suggested that a phenomenon called Break-Induced Replication (BIR) is responsible for several cancer related events, including chromosomal translocations, loss of heterozygosity, and stabilization of chromosomal ends. All three of these events lead to cellular immortalization. BIR, a poorly understood mechanism used by the cell to repair chromosomal breaks, is dangerous because it can lead to genetic rearrangements. The long-term goal of this research program is to understand the mechanism of BIR and how it is regulated by living cells to prevent genomic destabilization. The objectives of this particular application are to identify genes that carry out and regulate the BIR pathway and to determine the mechanism of gross chromosomal rearrangements associated with BIR. Yeast Saccharomyces cerevisiae will be used as a model eukaryotic system to study BIR. Genes involved in BIR will be identified by directly searching for mutants and also by testing known replication, recombination and checkpoint mutations to determine their effect on BIR. Chromosomal rearrangements will be examined by genomic microarray analysis! Also we will identify specific DMA motifs that stimulate rearrangements. The results of our proposed research will provide insights into the mechanism of Break-Induced Replication, its regulation, and how chromosomal rearrangements can occur as a result of BIR. This knowledge will provide a greater understanding of cancer etiology.