Mechanism of break-induced replication in yeast

描述（由申请人提供）：导致癌症的基因组重排的原因尚不完全清楚。最近有人提出，断裂诱导复制（BIR）现象导致了一些与癌症相关的事件，包括染色体易位、杂合性丧失和染色体末端的稳定。所有这三个事件导致细胞永生。BIR是细胞用来修复染色体断裂的一种鲜为人知的机制，它是危险的，因为它会导致基因重排。本研究计划的长期目标是揭示导致遗传不稳定的机制，特别是了解BIR的机制以及活细胞如何调节它以防止基因组不稳定。这一特殊应用的目标包括：与双链DNA断裂（DSBs）修复相关的总体染色体重排（GCRs）的特征，确定GCRs的BIR信息的作用，以及建立反向DNA重复序列在促进染色体重排中的作用。酿酒酵母将作为真核生物系统模型来研究dsb的修复。染色体重排将通过基因组微阵列分析进行检查。倒置DNA重复序列形成的分子中间体的物理分析将揭示这些DNA基序在促进gcr中的作用。我们提出的研究结果将为染色体重排的机制以及BIR和特定DNA基序在促进gcr中的作用提供见解。的相关性。这项拟议的研究旨在确定染色体畸变的潜在原因，这可能是不同类型癌症的机制。这项研究还将确定易导致染色体重排的遗传因素，因此，将导致改进筛选程序，旨在识别由于DNA修复异常模式而可能“有风险”罹患癌症的个体。

DESCRIPTION (provided by applicant): The causes of genomic rearrangements that lead to cancer are not fully understood. 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 cells to repair chromosomal breaks, is dangerous because it can lead to genetic rearrangements. The long-term goal of this research program is to uncover the mechanisms leading to genetic instability and, in particular, to understand the mechanism of BIR and how it is regulated by living cells to prevent genomic destabilization. The objectives of this particular application include: characterization of gross chromosomal rearrangements (GCRs) associated with repair of double-strand DNA breaks (DSBs), determining the role of BIR information of GCRs, and establishing the role of inverted DNA repeats in promoting chromosomal rearrangements. Yeast Saccharomyces cerevisiae will be used as a model eukaryotic system to study repair of DSBs. Chromosomal rearrangements will be examined by genomic microarray analysis. The physical analysis of molecular intermediates formed by inverted DNA repeats will reveal the role of these DNA motifs in promoting GCRs. The results of our proposed research will provide insights into the mechanisms of chromosomal rearrangements and the role of BIR and specific DNA motifs in promoting GCRs. Relevance. The proposed research is designed to determine the underlying cause of chromosomal aberrations that may be the mechanism for different types of cancer. This study will also identify genetic factors that predispose chromosomes to rearrangements and, therefore, will lead to improved screening procedures aimed to identify individuals who may be "at risk" for developing cancer due to abnormal patterns of DNA repair.