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.

项目概要 减数分裂过程中未能实现准确的染色体分离是导致减数分裂的主要原因 流产、不孕症和先天缺陷，如唐氏综合症。因此，了解 减数分裂过程中染色体精确分离的机制至关重要 对人类健康的重要性。联会复合体（SC）是一种拉链状结构 在从酵母到人类的减数分裂过程中普遍存在，并在 同源染色体稳定同源配对相互作用并促进 同源物间交叉形成。然而，尽管它对于关键事件的重要性 减数分裂过程中染色体的精确分离，染色体调节机制 突触在任何生物体中都没有被很好地理解。此外，研究的重点是后 形成这种结构的蛋白质的翻译调控揭示了 SC 的新作用， 将其与 DSB 形成和交叉指定的调节联系起来。这些最新发现 进一步强调该结构的重要性以及揭示其在过程中所发挥的作用 减数分裂。我们的目标是通过利用遗传的便利性来解决这些关键问题， 使用线虫 C 进行细胞学、分子和生化分析。 线虫，种系研究的理想模型系统。我们在上一次融资期间的进展 时期，再加上新的数据和分子目标，使我们处于一个理想的位置来理解 染色体突触的调节以及 SC 在减数分裂过程中发挥的作用。这里 我们提出两个综合目标来解决这些关键问题。目标 1 将解决如何 ATM/ATR 介导的 SYP-4 磷酸化（SC 的中心区域成分）调节 SC 动力学、DNA 双链断裂 (DSB) 修复以及交叉频率和分布。 目标 2 将确定 GRAS-1 的功能机制，GRAS-1 是一种新的保守蛋白 以前未知的减数分裂功能，我们的研究表明它与调节 SC 组装和 我们假设可能充当 SC 结构组件的分子支架。我们将 还研究了 GRAS-1 和哺乳动物 GRASP 之间共享的功能保守性 和 CYTIP 蛋白，通过对秀丽隐杆线虫和小鼠的联合研究。这些研究将揭示 我们对染色体突触调节机制的理解有了新的认识 SC 的角色。我们的研究预计将影响与以下领域密切相关的多个领域 人类健康，包括染色体动力学、翻译后修饰研究、 和大分子结构的调控。总而言之，该应用程序将提供 对调控精确染色体的分子机制的重要新见解 减数分裂期间的分离。