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Characterization of Genetic Instability at Chromosomal Fragile Sites

染色体脆弱位点遗传不稳定性的表征

基本信息

批准号：
7939329
负责人：
Anne Marie Casper
金额：
$ 43.18万
依托单位：
EASTERN MICHIGAN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2013-09-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Since a cell's DNA is frequently damaged by both external and internal agents, it is critical that such damage be accurately repaired. Damage that is not repaired, or that is repaired incorrectly, can result in mutation and genetic instability. In some cases, such alterations can lead to the development of cancer. Common fragile sites are one type of genomic element that may contribute to the development of cancer. There are 76 common fragile sites in the human genome and although these sites are normally stable, they are frequently broken and stimulate crossovers in cells that lack adequate amounts of DNA polymerase. Many types of tumors have been shown to contain deletions, amplifications, or translocations at fragile sites, therefore an understanding of the mechanisms contributing to this instability can aid understanding of cancer progression and prognosis. A naturally-occurring fragile site has been identified in the yeast Saccharomyces cerevisiae, named fragile site 2 (FS2), that mimics the type of genetic instability observed at human common fragile sites. This fragile site is a hotspot for double-strand breaks (DSBs) and translocations in cells with low levels of DNA polymerase. This proposal will use this simple eukaryote model system to build on and extend this work. The specific aims of the proposal are to: 1) Investigate the mechanism of DNA double-strand break formation at S. cerevisiae FS2, 2) investigate the stimulation of reciprocal mitotic crossovers at S. cerevisiae FS2, and 3) Investigate DNA double-strand break formation and crossover stimulation at human fragile site sequences using the yeast model system. These studies will help us understand which chromosome structures and sequences are intrinsically unstable, and what cellular pathways have a role in generating or repairing DSBs at such sites. This knowledge will help elucidate the mechanisms involved in genetic instability in tumor cells and further understand the genetic alterations contributing to the progression of cancer in humans. PUBLIC HEALTH RELEVANCE: Cancer cells have a high level of genetic instability, including large chromosome abnormalities such as rearrangements, amplifications, and deletions, and small changes such as the mutation of single bases. Naturally-occurring "fragile sites" on human chromosomes are correlated with genetic instability in cancer cells, but it is not well understood how and why these fragile sites generate instability. This proposal investigates instability at fragile sites from both yeast and human cells and will help elucidate some of the sequences, mechanisms, and proteins that have a role in genetic instability at these sites, which will add to the understanding of tumor development.

描述（由申请人提供）：由于细胞的DNA经常受到外部和内部因素的破坏，因此准确修复这种损害至关重要。没有修复的损伤，或者修复不正确的损伤，会导致突变和基因不稳定。在某些情况下，这种改变会导致癌症的发展。常见的脆弱位点是一种可能导致癌症发展的基因组元素。人类基因组中有76个常见的脆弱位点，尽管这些位点通常是稳定的，但它们经常被破坏，并在缺乏足够DNA聚合酶的细胞中刺激交叉。许多类型的肿瘤已被证明在脆弱位点包含缺失、扩增或易位，因此了解导致这种不稳定性的机制有助于了解癌症的进展和预后。在酿酒酵母中发现了一个自然发生的脆弱位点，命名为脆弱位点2 (FS2)，它模仿了在人类常见脆弱位点观察到的遗传不稳定性类型。在低水平DNA聚合酶的细胞中，这个脆弱的位点是双链断裂（DSBs）和易位的热点。本提案将使用这个简单的真核生物模型系统来建立和扩展这项工作。本研究的具体目的是：1)研究酿酒酵母FS2的DNA双链断裂形成机制，2)研究酿酒酵母FS2的有丝分裂交叉刺激，3)利用酵母模型系统研究人类脆弱位点序列的DNA双链断裂形成和交叉刺激。这些研究将帮助我们了解哪些染色体结构和序列本质上是不稳定的，以及哪些细胞途径在这些位点产生或修复dsb中起作用。这些知识将有助于阐明肿瘤细胞遗传不稳定的机制，并进一步了解促进人类癌症进展的遗传改变。