Regulation of Synaptonemal Complex Assembly During Meiosis in S. cerevisiae

酿酒酵母减数分裂过程中联会复合体组装的调控

• 批准号: 7449855
• 负责人: Amy Joy MacQueen
• 金额: $ 9万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7449855
• 关键词: Address; Alleles; Antibodies; Cell Nucleus; Cells; Centromere; Chromosome Pairing; Chromosome Segregation; Chromosomes; Defect; Diploidy; Disease; Down Syndrome; Ensure; Event; Exhibits; Failure; Frequencies; Genes; Genetic; Genetic Recombination; Germ Cells; HO nuclease; Hand; Homologous Gene; Human; In Vitro; Infertility; Lead; Learning; Length; Localized; Mammals; Measures; Mediating; Meiosis; Meiotic Recombination; Molecular; Mutation; Organism; Pathway interactions; Phenocopy; Phosphoric Monoester Hydrolases; Play; Positioning Attribute; Post-Translational Protein Processing; Preparation; Process; Prophase; Protein Overexpression; Proteins; Proteomics; Rate; Regulation; Reproduction spores; Reproductive Biology; Reproductive Health; Research; Role; Saccharomyces cerevisiae; Saccharomycetales; Screening procedure; Signal Pathway; Site; Structure; Synapses; Synaptonemal Complex; Transmission Electron Microscopy; Work; Yeasts; gel electrophoresis; homologous recombination; mutant; polymerization; prevent; research study

DESCRIPTION (provided by applicant): At the start of meiosis, chromosomes initiate an extensive reorganization that culminates in aligned homologous chromosomes, joined along their lengths by synaptonemal complex (SC), and each capable of undergoing recombination with its partner. This process is critical for accurate chromosome segregation during gamete formation in sexually reproducing organisms. Despite over a century of observing meiotic chromosome pairing and synapsis in diverse organisms, the molecular mechanisms underlying fundamental meiotic chromosomal events are still unknown. How do homologous chromosomes identify one another? How is this initial recognition reinforced? How is homolog recognition coordinated with SC assembly, such that synapsis occurs specifically between paired chromosomes? I have begun to investigate these questions by screening for factors that regulate SC assembly in budding yeast. I identified roles for two factors in SC regulation. The FPR3 gene promotes the formation of polycomplexes in nuclei that are defective in homolog alignment. Polycomplexes are focal accumulations of SC components that reflect a failure in SC polymerization on chromosomes, and frequently occur in mutants with early meiotic defects in pairing or recombination. ZIPS, on the other hand, plays a role in preventing SC assembly on chromosomes. When polycomplex formation is compromised and ZIPS activity is missing, (as in a zipS fprS double mutant), SC components polymerize on chromosomes, independent of homolog alignment. Interestingly, the linear SC structures that arise in zipS fprS nuclei originate from centromere regions. As ZipS colocalizes with the SC structural component, Zip1, at centromere regions prior to homolog alignment, perhaps ZipS contributes to reinforcing homolog recognition by regulating SC assembly at centromeres. The experiments proposed use genetic, cytological and proteomic approaches to ask: How do FPRS and ZIPS regulate SC assembly? What is the molecular relationship between SC assembly, recombination and homolog pairing? The proposed research aims to understand basic cellular mechanisms that control meiotic chromosome processes that are conserved between yeast and mammals. As meiotic chromosome segregation defects lead to infertility and disorders such as Down's Syndrome, it is hoped that what is learned from my research may play a role in understanding, treating, and nurturing human reproductive health.

描述（由申请人提供）：在减数分裂开始时，染色体启动广泛的重组，最终形成对齐的同源染色体，通过联会复合体（SC）沿其长度连接，并且每条染色体都能够与其伴侣进行重组。这一过程对于有性生殖生物体配子形成过程中染色体的准确分离至关重要。尽管在不同生物体中观察减数分裂染色体配对和突触已有一个多世纪的历史，但基本减数分裂染色体事件背后的分子机制仍然未知。同源染色体如何相互识别？这种最初的认知是如何被强化的？同源识别如何与 SC 组装协调，使得突触发生在配对染色体之间？我已经开始通过筛选调节芽殖酵母 SC 组装的因子来研究这些问题。我确定了两个因素在 SC 调节中的作用。 FPR3 基因促进同源比对缺陷的细胞核中多聚复合物的形成。多复合物是 SC 成分的集中积累，反映了染色体上 SC 聚合的失败，并且经常发生在配对或重组中具有早期减数分裂缺陷的突变体中。另一方面，ZIPS 则在阻止 SC 在染色体上组装方面发挥着作用。当多复合物形成受到损害且 ZIPS 活性缺失时（如 zipS fprS 双突变体），SC 成分在染色体上聚合，与同源比对无关。有趣的是，zipS fprS 核中出现的线性 SC 结构源自着丝粒区域。由于 ZipS 在同源比对之前与 SC 结构成分 Zip1 共定位于着丝粒区域，因此 ZipS 可能通过调节着丝粒处的 SC 组装来增强同源识别。实验建议使用遗传、细胞学和蛋白质组学方法来询问：FPRS 和 ZIPS 如何调节 SC 组装？ SC组装、重组和同源配对之间的分子关系是什么？拟议的研究旨在了解控制酵母和哺乳动物之间保守的减数分裂染色体过程的基本细胞机制。由于减数分裂染色体分离缺陷会导致不孕症和唐氏综合症等疾病，因此希望我的研究成果能够在理解、治疗和培育人类生殖健康方面发挥作用。