Checkpoint protein interactions with a fragile site and chromosome instability

检查点蛋白与脆弱位点的相互作用和染色体不稳定性

• 批准号: 7261364
• 负责人: TED A. WEINERT
• 金额: $ 28.15万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7261364
• 关键词: Affect; Cells; Chromosomal Instability; Chromosomal translocation; Chromosome Fragile Sites; Chromosomes; DNA; DNA Sequence Rearrangement; DNA biosynthesis; DNA replication fork; Defect; Ensure; Event; Genes; Genetic; Genetic Recombination; Genome; Genome Stability; Genomic Instability; Goals; Joints; Lead; Link; Metabolism; Molecular Genetics; Normal Cell; Outcome; Pathway interactions; Process; Proteins; Reaction; Recombinants; Research; Role; Saccharomycetales; Site; Structure; System; Testing; Transfer RNA; Yeasts; cancer cell; genetic regulatory protein; helicase; interest; mutant; novel; prevent

DESCRIPTION (provided by applicant): The overall goal of our research is to understand how checkpoint proteins regulate genome stability. We propose to study checkpoint proteins and instability arising at one chromosomal site that behaves like a fragile site. We found that the yeast fragile site behaves very much like a mammalian fragile site; both yeast and mammalian sites appear to stall replication forks, and both activate and are then stabilized by interaction with checkpoint proteins. We believe that study of the yeast fragile site provides a unique opportunity to understand mammalian fragile sites as well as to study events that link stalled replication forks to genome instability at many chromosomal sites. We have developed an experimental system to study this site, and believe its instability is due to stalling and breakage of DNA replication forks that is greatly enhanced in checkpoint mutants. Specifically, we propose that the initial event at this site is the stalling of DNA replication by tRNA genes. Second, we propose that the stalled forks collapse or break. Third, we propose that DNA breaks undergo non-allelic recombination with other chromosomal sites (that may also be fragile) to generate unstable translocations. Fourth, we propose the unstable translocation is unstable because it has a "hyperfragile" joint prone to additional rearrangements (cycles of instability). Finally, we propose that checkpoint and other regulatory proteins regulate fork stalling, breakage, and recombination to influence the sites instability. We believe that understanding each of these events at this site will be informative for understanding how such events occur at many sites in the genome. Completion of these studies will contribute to our understanding of how checkpoint proteins maintain genome stability. Checkpoints are cellular controls that ensure that chromosomes are correctly duplicated. Understanding how checkpoints keep a cell's genome intact is critical to understanding the process of how a normal cell becomes a cancer cell.

描述（由申请人提供）：我们研究的总体目标是了解检查点蛋白如何调节基因组稳定性。我们建议在一个像脆弱部位的染色体部位研究检查点蛋白质和不稳定性。我们发现酵母菌部位的行为非常像哺乳动物脆弱的部位。酵母和哺乳动物位点似乎都停滞了复制叉，并且都通过与检查点蛋白的相互作用而稳定了激活。我们认为，对酵母菌部位的研究为了解哺乳动物脆弱的位点以及研究将停滞的复制叉与许多染色体部位的基因组不稳定性联系起来的事件提供了独特的机会。我们已经开发了一个实验系统来研究该站点，并认为其不稳定性是由于DNA复制叉的停滞和破裂而导致的，该复制叉在检查点突变体中大大增强。具体而言，我们建议该站点的初始事件是tRNA基因复制的停滞。其次，我们提出停滞的叉子倒塌或破裂。第三，我们建议DNA断裂与其他染色体位点（也可能是脆弱）进行非平行性重组以产生不稳定的易位。第四，我们提出不稳定的易位是不稳定的，因为它具有易于重排的“超浮动”关节（不稳定性的循环）。最后，我们建议检查点和其他调节蛋白调节叉档，断裂和重组以影响站点不稳定。我们认为，了解本网站上的每一个事件都将为您了解基因组中许多地点发生此类事件的方式。这些研究的完成将有助于我们对检查点蛋白如何保持基因组稳定性的理解。检查点是细胞对照，可确保正确复制染色体。了解检查点如何保持细胞的基因组完整对于理解正常细胞如何成为癌细胞的过程至关重要。