Homologous chromosome pairing during meiosis in yeast

酵母减数分裂过程中的同源染色体配对

• 批准号: 7476512
• 负责人: Sean M Burgess
• 金额: $ 27.28万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7476512
• 关键词: Address; Affect; Anaphase; Aneuploidy; Base Pairing; Biological Assay; Candidate Disease Gene; Cells; Chromatin; Chromatin Structure; Chromosome Pairing; Chromosome Segregation; Chromosome Structures; Chromosomes; Condition; Congenital Abnormality; DNA biosynthesis; DNA chemical synthesis; DNA damage checkpoint; Defect; Dose; Double Strand Break Repair; Down Syndrome; Embryo; Enzymatic Biochemistry; Event; Frequencies; Future Generations; Gene Mutation; Genes; Genetic Recombination; Genome; Genomics; Germ Cells; Health; Homologous Gene; Hot Spot; Human; Kinetics; Lead; Link; Measures; Meiosis; Meiotic Prophase I; Meiotic Recombination; Molecular Genetics; Motion; Movement; Nuclear Envelope; Numbers; Pathway interactions; Pharmaceutical Preparations; Phenotype; Positioning Attribute; Pregnancy loss; Process; Protein Binding; Proteins; Relative (related person); Reporting; Research; Research Personnel; Role; Saccharomycetales; Site; Spottings; Structure; System; Telomere Recombination; Telomere-Binding Proteins; Testing; Variant; Yeasts; cancer cell; cell type; chromatin immunoprecipitation; chromatin remodeling; chromosome movement; egg; homologous recombination; mutant; programs; repaired; research study; segregation; sperm cell; telomere; tool

DESCRIPTION (provided by applicant): Our objective is to understand how homologous recombination and telomere organization contribute to the juxtaposition of homologous chromosomes in meiosis. These processes are essential to proper chromosome segregation at anaphase I. Defects in these processes can lead to aneuploid gametes, which contribute to birth defects in humans. Mechanisms underlying these processes (double-strand break repair, telomere integrity and chromosome organization) contribute directly to the genesis of cancer cells. How homologs pair is a major unanswered question in the study of meiosis. We propose experiments using budding yeast to address two central questions: i) to what extent do base-pairing interactions contribute to the ability of homologous chromosomes to find one another? And ii) what defines the mechanistic link between dynamic organization of telomeres, recombination, and close, stable homolog juxtaposition (CSHJ). Our hypothesis is that a specific mechanistic step of recombination depends in part on telomere integrity, position or motion. This step is the stabilization of strand-invasion intermediates. A telomere-bound protein, Ndj1, is involved in linking telomere function to chromosome recombination and segregation in meiosis. We propose roles for chromatin structure and DNA damage checkpoint proteins in achieving CSHJ. 1. We will determine the mechanistic step(s) in meiotic recombination that lead to CSHJ. We will use a new quantitative assay that reports on the relative spatial position or accessibility of two chromosomal loci. 2. We will determine the specific features of meiotic telomere reorganization that impact meiotic recombination. We will explore the potential roles of spatial constraint, chromosome motion and a possible direct role in recombination by Ndj1 or other known telomere-bound proteins. 3. We will identify genes by mutation that act in concert with Ndj1 to promote the stabilization of strand invasion intermediates. Genome-wide and candidate gene approaches will be taken. Lay description: Pregnancy loss and birth defects result from embryos having abnormal chromosome numbers (e.g. trisomy 21 or Downs syndrome). This research focuses on understanding how chromosomes are properly distributed to sperm and egg cells. Our findings will impact health of future generations.

描述（由申请人提供）：我们的目的是了解同源重组和端粒组织如何有助于减数分裂中同源染色体的并列。这些过程对于后期I染色体的正确分离是必不可少的。这些过程中的缺陷会导致非整倍体配子，这会导致人类的出生缺陷。这些过程的机制（双链断裂修复，端粒完整性和染色体组织）直接有助于癌细胞的发生。同源染色体如何配对是减数分裂研究中一个尚未解决的问题。我们提出使用芽殖酵母的实验来解决两个中心问题：i）碱基配对相互作用在多大程度上有助于同源染色体找到彼此的能力？以及ii）什么定义了端粒的动态组织，重组和紧密稳定的同源并置（CSHJ）之间的机械联系。我们的假设是，一个特定的机械步骤重组部分取决于端粒的完整性，位置或运动。这一步是稳定链侵入中间体。端粒结合蛋白Ndj1参与将端粒功能与减数分裂中的染色体重组和分离联系起来。我们提出了染色质结构和DNA损伤检查点蛋白在实现CSHJ中的作用。1.我们将确定减数分裂重组中导致CSHJ的机制步骤。我们将使用一种新的定量分析，报告两个染色体位点的相对空间位置或可及性。2.我们将确定影响减数分裂重组的减数分裂端粒重组的具体特征。我们将探讨空间约束，染色体运动的潜在作用和可能的直接作用在重组Ndj1或其他已知的端粒结合蛋白。3.我们将通过与Ndj1协同作用以促进链侵入中间体稳定的突变来鉴定基因。将采用全基因组和候选基因方法。简单描述：胚胎染色体数目异常（如21三体或唐斯综合征）导致妊娠丢失和出生缺陷。这项研究的重点是了解染色体如何正确分布到精子和卵细胞。我们的研究结果将影响后代的健康。