Genetic regulation of genome stability in yeast

酵母基因组稳定性的遗传调控

• 批准号: 7448623
• 负责人: THOMAS PETES
• 金额: $ 37.87万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-05-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7448623
• 关键词: ATM gene; ATR gene; Affect; Aphidicolin; Base Pairing; Cell Cycle; Chromatin Modeling; Chromosomal Breaks; Chromosome Fragile Sites; Chromosome Structures; Chromosome abnormality; Chromosomes; DNA; DNA Microarray Chip; DNA Microarray format; DNA Polymerase Inhibitor; DNA Sequence; DNA Sequence Rearrangement; DNA damage checkpoint; Diploidy; Event; Evolution; Fungal Genome; Gel; Gene Dosage; Genes; Genetic; Genetic Recombination; Genome; Genome Stability; Genomic Instability; Genomics; Genotype; Goals; Homologous Gene; Investigation; Ionizing radiation; Length; Malignant Neoplasms; Mammalian Cell; Maps; Microarray Analysis; Mutation; Neoplasm Metastasis; Ploidies; Polymerase; Positioning Attribute; Process; Property; Rate; Regulation; Research; Saccharomyces; Saccharomyces cerevisiae; Site; Techniques; Technology; Temperature; Translocation Breakpoint; Yeasts; irradiation; mutant; neoplastic cell; rRNA Genes; telomere

DESCRIPTION (provided by applicant): Genomes can be altered in a variety of ways including single base pair changes, deletions and duplications of sequences, and chromosome rearrangements (translocations and inversions). The rates at which these events occur affect 2 quite different processes. Genetic changes are required for evolution and the rate of these changes, therefore, can in principle affect the rate of evolution. Second, many cancers are associated with elevated rates of chromosome rearrangements, and this type of instability appears to be strongly associated with metastatic tumors. When mammalian cells are treated with aphidicolin (a DNA polymerase inhibitor), the chromosomes are broken at specific sites (fragile sites) that are related to translocation breakpoints observed in tumor cells. High levels of chromosome breaks and other aberrations are also observed in mammalian cells with mutations in the ATM and ATR genes. Our general goal is to mimic this type of genetic instability in the yeast Saccharomyces cerevisae, and to characterize the mechanisms responsible for this instability. Our specific aims are: 1) to determine the DNA sequence properties that characterize yeast fragile sites and to characterize the chromosome rearrangements that are associated with DNA breaks at fragile sites, 2) to characterize chromosome aberrations in yeast strains with mutations in genes affecting DNA damage checkpoints, telomere length regulation, recombination, and/or chromatin assembly; for example, strains with mec1 and/or tel1 genes (yeast homologues of the mammalian ATR and ATM genes, respectively) will be examined, and 3) to understand the genetic instability induced by ionizing radiation. These studies will emphasize techniques that allow examination of the entire yeast genome, including DNA microarray analysis (to detect changes in gene dosage and to map translocation breakpoints), and gel technologies that allow separation of intact chromosomal DNA molecules.

描述（由申请人提供）：基因组可以以多种方式改变，包括单碱基对改变、序列缺失和重复以及染色体重排（易位和倒位）。这些事件发生的速率影响两个完全不同的过程。遗传变化是进化所必需的，因此，这些变化的速度原则上会影响进化的速度。其次，许多癌症与染色体重排率升高有关，这种类型的不稳定性似乎与转移性肿瘤密切相关。当哺乳动物细胞用阿非迪霉素（一种DNA聚合酶抑制剂）处理时，染色体在与肿瘤细胞中观察到的易位断点相关的特定位点（脆性位点）断裂。在ATM和ATR基因突变的哺乳动物细胞中也观察到高水平的染色体断裂和其他畸变。我们的总体目标是模仿这种类型的遗传不稳定性的酵母酿酒酵母，并表征负责这种不稳定性的机制。我们的具体目标是：1）确定表征酵母脆性位点的DNA序列性质，并表征与脆性位点处的DNA断裂相关的染色体重排，2）表征具有影响DNA损伤检查点、端粒长度调节、重组和/或染色质组装的基因突变的酵母菌株中的染色体畸变;例如，将检查具有mec 1和/或tel 1基因（分别是哺乳动物ATR和ATM基因的酵母同源物）的菌株，以及3）了解电离辐射诱导的遗传不稳定性。这些研究将强调允许检查整个酵母基因组的技术，包括DNA微阵列分析（以检测基因剂量的变化并绘制易位断点），以及允许分离完整染色体DNA分子的凝胶技术。