Molecular mechanisms of chromosome organization and recombination control by the meiotic chromosome axis

减数分裂染色体轴染色体组织和重组控制的分子机制

• 批准号: 10387324
• 负责人: Kevin Daniel Corbett
• 金额: $ 7.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-10 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10387324
• 关键词: ATP phosphohydrolase; Aneuploidy; Biochemical; Biochemistry; Biological; Cells; Chromatin Loop; Chromosome Segregation; Chromosome Structures; Chromosomes; Complex; DNA; DNA Binding; DNA Repair Pathway; Diploidy; Disease; Down Syndrome; Environment; Eukaryota; Excision; Family; Feedback; Filament; Foundations; Generations; Genetic; Genetic Recombination; Genome; Genomic Instability; Germ Cells; Haploidy; Health; Homologous Gene; Human; Human Chromosomes; Knowledge; Lead; Learning; Link; Live Birth; Malignant Neoplasms; Mediating; Meiosis; Meiotic Recombination; Molecular; Molecular Conformation; Molecular Machines; Morphology; Mus; Pathway interactions; Ploidies; Pregnancy; Prophase; Proteins; Reproduction; Role; Saccharomyces cerevisiae; Sexual Reproduction; Source; Specificity; Spontaneous abortion; Structure; Testing; Turner' s Syndrome; Work; cancer cell; cancer type; chromosome loss; cohesin; developmental disease; egg; homologous recombination; member; offspring; protein complex; recruit; segregation; sperm cell; ATP phosphohydrolase; Aneuploidy; Biochemical; Biochemistry; Biological; Cells; Chromatin Loop; Chromosome Segregation; Chromosome Structures; Chromosomes; Complex; DNA; DNA Binding; DNA Repair Pathway; Diploidy; Disease; Down Syndrome; Environment; Eukaryota; Excision; Family; Feedback; Filament; Foundations; Generations; Genetic; Genetic Recombination; Genome; Genomic Instability; Germ Cells; Haploidy; Health; Homologous Gene; Human; Human Chromosomes; Knowledge; Lead; Learning; Link; Live Birth; Malignant Neoplasms; Mediating; Meiosis; Meiotic Recombination; Molecular; Molecular Conformation; Molecular Machines; Morphology; Mus; Pathway interactions; Ploidies; Pregnancy; Prophase; Proteins; Reproduction; Role; Saccharomyces cerevisiae; Sexual Reproduction; Source; Specificity; Spontaneous abortion; Structure; Testing; Turner' s Syndrome; Work; cancer cell; cancer type; chromosome loss; cohesin; developmental disease; egg; homologous recombination; member; offspring; protein complex; recruit; segregation; sperm cell

PROJECT SUMMARY Sexual reproduction in eukaryotes involves the generation of haploid gametes (in humans, sperm and egg cells) in meiosis, followed by the fusion of two gametes to produce diploid offspring. In meiosis, homologous chromosomes recognize one another and become physically linked through a modified homologous recombination DNA repair pathway, and the resulting crossovers enable accurate homolog segregation in the meiosis I division to reduce ploidy. In most eukaryotes including humans, chromosomes are organized as an array of chromatin loops by a highly conserved structure called the chromosome axis. The chromosome axis also recruits and controls DNA cleavage and recombination factors to mediate the formation of crossovers, and is remodeled after crossover formation in a key feedback pathway controlling recombination levels. Here, we propose to combine biochemistry, structure, and genetics in S. cerevisiae and the mouse to determine how the chromosome axis assembles, organizes chromosomes, and mediates crossover formation. We will determine the structures of S. cerevisiae Red1 and mammalian SYCP2:SYCP3, functionally-related chromosome axis “foundation” proteins that we have found share a conserved domain structure and propensity to self-assemble into filaments. We will next determine how these proteins interact with meiotic cohesin complexes, to understand the structural basis for axis-mediated chromosome organization. Next, we will dissect the network of interactions mediated by S. cerevisiae Hop1, a member of the conserved HORMAD family and a master regulator of meiotic recombination, and study how this interaction network changes during meiotic prophase. Hop1’s eventual removal from the chromosome axis, an important feedback pathway controlling recombination levels, is mediated by the AAA+ ATPase Pch2. We will test our hypothesis that Pch2 directly recognizes a specific Hop1 conformation and partially unfolds its HORMA domain to mediate its removal from the axis. Finally, we will examine the structures, DNA binding specificity, and interactions of two meiosis-specific protein complexes, Msh4:Msh5 and Zip2:Zip4:Spo16, to learn how they stabilize specific DNA recombination intermediates and coordinate crossover formation with chromosome axis morphology changes. Overall, the work proposed here will result in a comprehensive molecular picture of how the chromosome axis assembles, coordinates crossover formation, and is then disassembled as recombination proceeds. Understanding the molecular mechanisms of the chromosome axis and associated factors is highly relevant to human health, as errors in meiotic chromosome segregation are a principal cause of miscarriage in humans, and are the source of “aneuploidy disorders” like Down syndrome and Turner syndrome. Moreover, many cancer types show mis-expression of meiotic chromosome axis proteins, including TRIP13, HORMAD1, and SYCP2. A better understanding of these proteins’ mechanisms in their native environment will be critical to determine how their mis-expression might lead to genome instability and cancer.

项目摘要 真核生物的有性繁殖涉及单倍体游戏的产生（人类，精子和鸡蛋 细胞）减数分裂，然后融合了两个游戏，以产生二倍体后代。在减数分裂中，同源 染色体互相识别，并通过修改的同源物进行身体联系 重组DNA修复途径，由此产生的交叉使得在 减数分裂I分裂以减少倍性。在包括人类在内的大多数真核生物中，染色体被组织为 通过高度组成的结构称为染色体轴，染色质环路阵列。 还招募和控制DNA裂解和重组因子，以介导跨界的形成，并 在控制重组水平的关键反馈途径中进行了交叉形成后进行重塑。 在这里，我们建议在酿酒酵母和小鼠中结合生物化学，结构和遗传学 确定染色体轴如何组装，组织染色体并介导交叉形成。 我们将确定酿酒酵母红色1和哺乳动物sycp2：Sycp3的结构，功能相关 我们发现的染色体轴“粉底”蛋白具有共享构成的域结构和承诺 自我组装成细丝。接下来，我们将确定这些蛋白质如何与减数分裂粘着蛋白相互作用 复合物，了解轴介导的染色体组织的结构基础。接下来，我们会的 剖析酿酒酵母霍普1介导的相互作用网络，这是保守的激素的成员 家庭和减数分裂重组的主要调节剂，并研究此相互作用网络如何变化 减数分裂的预言。 Hop1最终从染色体轴上移除，这是一个重要的反馈途径 控制重组水平是由AAA+ ATPase PCH2介导的。我们将测试PCH2的假设 直接认可特定的Hop1会议，并部分展开其Horma领域以调解其 从轴上卸下。最后，我们将检查两个结构，DNA结合特异性和两个的相互作用 减数分裂特异性蛋白质复合物，MSH4：MSH5和Zip2：Zip4：Spo16，以了解它们如何稳定特定的DNA 重组中间体并将交叉形成与染色体轴形态变化。 总体而言，此处提出的工作将导致全面的分子图片，说明染色体轴如何 组装，协调跨界形成，然后随着重组的进行而拆卸。 了解染色体轴和相关因素的分子机制与 人类健康，作为减数分裂染色体隔离的错误是人类流产的主要原因， 并且是唐氏综合症和特纳综合症等“非整倍性疾病”的来源。而且，许多 癌症类型表现出减数分裂染色体轴蛋白的不良表达，包括Trip13，Hormad1和 SYCP2。更好地理解这些蛋白质在其本地环境中的机制对于 确定它们的表达方式可能导致基因组不稳定性和癌症。