Synaptonemal complex assembly and function in meiosis

项目摘要 在减数分裂期间未能实现准确的染色体分离是流产的主要原因， 不孕症和先天缺陷，如唐氏综合症。因此，了解其机制 在减数分裂过程中准确的染色体分离对人类健康至关重要。的 联会复合体（synaptonemal complex，SC）是一种拉链样结构，广泛存在于从酵母到人类的减数分裂过程中 在那里它在同源染色体之间组装，稳定同源配对相互作用， 促进同源物间交换形成。然而，尽管它对关键事件的重要性， 在减数分裂期间染色体精确分离，调节染色体联会的机制并不 在任何生物体中都很容易理解。此外，研究集中在蛋白质的翻译后调控 这种结构的形成揭示了SC的新作用，将其与DSB形成的调节联系起来， 交叉命名。这些最近的调查结果进一步强调了这一结构的重要性， 揭示它在减数分裂中的作用。我们的目标是通过利用 通过使用线虫提供的遗传、细胞学、分子和生物化学分析的容易性 C. elegans是种系研究的理想模型系统。我们在上一个融资期取得的进展， 新的数据和分子靶点，使我们处于一个理想的位置，以了解染色体的调控 突触和SC在减数分裂过程中发挥的作用。在这里，我们提出了两个综合目标，以解决这些问题 关键问题。目的1将阐明ATM/ATR介导的SYP-4磷酸化， SC的组成部分，调节SC动力学，DNA双链断裂（DSB）修复和交叉频率 和分配。目的二是研究GRAS-1蛋白的功能机制，GRAS-1蛋白是一种新的、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，我们假设 可以作为SC结构成分的分子支架。我们还将研究SC的功能， GRAS-1与哺乳动物GRASP和CYTIP蛋白之间共有的保守性，通过联合研究 in C.线虫和老鼠这些研究将为我们理解调节细胞凋亡的机制提供新的思路。 染色体突触和SC的作用。我们的研究预计将影响多个领域的巨大 与人类健康的相关性，包括染色体动力学，翻译后修饰的研究， 大分子结构的调节。总的来说，这个应用程序将提供重要的新见解， 减数分裂中染色体精确分离的分子机制。

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.