Mechanisms of Chromosome Breakage and Rearrangements Induced by Repeats that Adopt DNA Secondary Structures

采用 DNA 二级结构的重复序列诱导染色体断裂和重排的机制

• 批准号: 0417088
• 负责人: Kirill Lobachev
• 金额: $ 67.39万
• 依托单位: Georgia Tech Research Corporation
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2008-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0417088&HistoricalAwards=false
• 关键词: Mechanisms; Chromosome; Breakage; Rearrangements; Induced

Mechanisms of Chromosome Breakage and Rearrangements Induced by Repeats that Adopt DNA Secondary Structures Chromosomes of many eukaryotic organisms including humans contain a large number of repetitive sequences. Several types of commonly present DNA repeats can be arranged in sequence motifs which are able to adopt hairpin and cruciform secondary structures. Inverted repeats, AT- and GC-rich micro- and minisatellites comprising this class of sequence motifs are frequently found in chromosomal regions that are prone to gross rearrangements such as translocations, deletions, inversions and amplifications. Recent studies indicate that a double-strand break (DSB) occurring at the sites of the inverted repeats (IRs) and long tracks of CTG/CAG triplet repeats can be an initial event in generation of chromosome rearrangements. However, little is currently known about the mechanisms underlying this type of genetic instability. The overall goal of this study is to understand the mechanisms by which repeats that have potential to form hairpins and cruciforms can initiate DSB's and subsequent chromosome aberrations. The study will be done using a newly developed model system in the yeast Saccharomyces cerevisiae. The specific objectives are (1) to determine the molecular mechanisms by which hairpin- or cruciform-associated DSB's lead to gross chromosomal rearrangements; and (2) to identify genetic pathways that contribute to DSB formation at the sites of unstable repeats. The information obtained as a result of this research will improve the knowledge of molecular events responsible for chromosome instability. The research heavily relies on the active participation of undergraduate and graduate students. The research team carrying out this study is expected to include female researchers and minorities, who will be recruited from the student population at Georgia Institute of Technology.

采用DNA二级结构的重复序列诱导染色体断裂和重排的机制包括人类在内的许多真核生物的染色体都含有大量的重复序列。几种常见的DNA重复序列可以排列在序列基序中，这些基序可以采用发夹和十字形二级结构。包含这类序列基序的反向重复序列、富含AT和GC的微卫星和小卫星经常发现于倾向于总重排如易位、缺失、倒位和扩增的染色体区域中。最近的研究表明，在CTG/CAG三联体重复序列的反向重复序列（IR）和长轨道上发生的双链断裂（DSB）可能是染色体重排产生的起始事件。然而，目前对这种遗传不稳定性的机制知之甚少。本研究的总体目标是了解有可能形成发夹和十字形的重复序列启动DSB和随后的染色体畸变的机制。这项研究将使用一个新开发的模型系统在酵母酿酒酵母。具体目标是（1）确定发夹或十字形相关DSB导致总染色体重排的分子机制;和（2）鉴定有助于在不稳定重复位点形成DSB的遗传途径。 作为这项研究的结果获得的信息将提高负责染色体不稳定性的分子事件的知识。这项研究在很大程度上依赖于本科生和研究生的积极参与。进行这项研究的研究小组预计将包括女性研究人员和少数民族，他们将从格鲁吉亚理工学院的学生中招募。