Synaptonemal complex assembly and function in meiosis

减数分裂中的联会复合体组装和功能

• 批准号: 10409402
• 负责人: Monica P Colaiacovo
• 金额: $ 6.24万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10409402
• 关键词: Address; Biochemical; Biological Models; Caenorhabditis elegans; Cell division; Chromosome Pairing; Chromosome Segregation; Chromosomes; Congenital Abnormality; Coupled; Cytology; DNA Double Strand Break; Data; Development; Double Strand Break Repair; Down Syndrome; Event; Failure; Foundations; Frequencies; Funding; Genetic; Goals; Health; Human; Infertility; Light; Link; Mediating; Meiosis; Molecular; Molecular Structure; Molecular Target; Mus; Nematoda; Organism; Phosphorylation; Play; Positioning Attribute; Post-Translational Protein Processing; Post-Translational Regulation; Prevention strategy; Proteins; Regulation; Reproductive Health; Role; Spontaneous abortion; Structure; Synaptonemal Complex; Yeasts; egg; insight; novel; programs; scaffold; sperm cell

PROJECT SUMMARY Failure to achieve accurate chromosome segregation during meiosis is a leading cause of miscarriages, infertility, and birth defects such as Down syndrome. Therefore, understanding the mechanisms underlying accurate chromosome segregation during meiosis is of paramount importance to human health. The synaptonemal complex (SC) is a zipper-like structure ubiquitously present during meiosis from yeast to humans where it assembles between homologous chromosomes stabilizing homologous pairing interactions and promoting interhomolog crossover formation. However, despite its importance for key events required for accurate chromosome segregation during meiosis, the mechanisms regulating chromosome synapsis are not well understood in any organism. Moreover, studies focused on the post- translational regulation of proteins forming this structure are uncovering novel roles for the SC, linking it to the regulation of DSB formation and crossover designation. These recent findings further underscore the importance of this structure and of uncovering the roles it plays during meiosis. Our goal is to address these critical issues by taking advantage of the ease of genetic, cytological, molecular and biochemical analysis that is afforded by the use of the nematode C. elegans, an ideal model system for germline studies. Our progress during the previous funding period, coupled with new data and molecular targets, place us in an ideal position to understand the regulation of chromosome synapsis and the roles exerted by the SC during meiosis. Here we propose two integrated aims to address these critical issues. Aim 1 will address how ATM/ATR-mediated phosphorylation of SYP-4, a central region component of the SC, regulates SC dynamics, DNA double-strand break (DSB) repair, and crossover frequency and distribution. Aim 2 will determine the mechanisms of function for GRAS-1, a new and conserved protein of previously unknown meiotic function, which our studies implicate in regulating SC assembly and we hypothesize may act as a molecular scaffold for structural components of the SC. We will also investigate the functional conservation shared between GRAS-1 and mammalian GRASP and CYTIP proteins, through combined studies in C. elegans and mice. These studies will shed new light on our understanding of the mechanisms regulating chromosome synapsis and the roles of the SC. Our studies are expected to impact multiple fields of tremendous relevance to human health including chromosome dynamics, the study of post-translational modifications, and regulation of macromolecular structures. Taken together, this application will provide significant new insights into the molecular mechanisms regulating accurate chromosome segregation during meiosis.

项目摘要 减数分裂期间未能实现准确的染色体分离是主要原因 流产，不育症和出生缺陷，例如唐氏综合症。因此，了解 减数分裂过程中准确的染色体分离的机制至关重要 对人类健康的重要性。突发型复合物（SC）是一种拉链样结构 从酵母到人类的减数分裂过程中无处不在 同源染色体稳定同源配对相互作用并促进 人体间交叉形成。但是，尽管它对需要关键事件的重要性 在减数分裂过程中，准确的染色体分离，调节染色体的机制 突触在任何生物体中都不是很好的理解。此外，研究重点是 形成这种结构的蛋白质的翻译调节是发现SC的新作用， 将其与DSB形成和交叉指定的调节联系起来。这些最近的发现 进一步强调了这种结构的重要性以及揭示其在 减数分裂。我们的目标是通过利用遗传的易用性来解决这些关键问题 使用线虫C提供的细胞学，分子和生化分析可提供。 秀丽隐杆线，一种用于种系研究的理想模型系统。我们在以前的资金中的进步 期间，再加上新数据和分子目标，将我们置于理想的位置 染色体突触的调节和SC在减数分裂过程中扮演的角色。这里 我们提出了两个综合目的，以解决这些关键问题。 AIM 1将解决如何 SC的中心区域SYP-4的ATM/ATR介导的磷酸化调节 SC动力学，DNA双链断裂（DSB）修复以及交叉频率和分布。 AIM 2将确定GRAS-1的功能机理，GRAS-1是一种新的和保守的蛋白质 以前未知的减数分裂功能，我们的研究涉及调节SC组装和 我们假设可以充当SC结构成分的分子支架。我们将 还研究GRAS-1和哺乳动物掌握之间共享的功能保护 通过在秀丽隐杆线虫和小鼠中进行的联合研究和细胞蛋白。这些研究将丢弃 我们对调节染色体突触的机制的理解的新灯 SC的角色。我们的研究有望影响与 人类健康，包括染色体动力学，翻译后修饰的研究， 和大分子结构的调节。综上所述，该申请将提供 对调节准确染色体的分子机制的重要新见解 减数分裂过程中的隔离。