Mechanism of break-induced replication in yeast

描述（由申请人提供）：在理解导致癌症的基因组重排的原因方面存在差距。最近有人提出，一种称为断裂诱导复制（BIR）的现象是导致几种癌症相关事件的原因，包括染色体易位、杂合性丢失和染色体末端稳定。所有这三个事件导致细胞永生化。BIR是细胞用来修复染色体断裂的一种知之甚少的机制，它是危险的，因为它可能导致基因重排。该研究计划的长期目标是了解BIR的机制以及活细胞如何调节它以防止基因组不稳定。该特定应用的目的是鉴定进行和调节BIR途径的基因，并确定与BIR相关的总染色体重排的机制。酿酒酵母将被用作研究BIR的真核生物模型系统。将通过直接搜索突变体以及通过测试已知的复制、重组和检查点突变以确定其对BIR的影响来鉴定涉及BIR的基因。染色体重排将通过基因组微阵列分析进行检查！我们还将确定刺激重排的特定DMA基序。我们拟议的研究结果将为断裂诱导复制的机制、其调节以及BIR如何导致染色体重排提供见解。这些知识将提供对癌症病因学的更好理解。

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.