Synaptonemal complex assembly and function in meiosis

项目摘要 在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、不孕和先天缺陷，如唐氏综合症。因此了解 在减数分裂过程中，染色体精确分离的机制是至关重要的 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， 同源染色体稳定同源配对相互作用和促进 同源物间交叉形成。然而，尽管它对关键事件的重要性， 减数分裂过程中染色体的精确分离， 在任何生物体中，突触都不是很清楚。此外，研究集中在后- 形成这种结构的蛋白质的翻译调节揭示了SC的新作用， 将其与DSB形成和交叉指定的调节联系起来。这些最新的发现 进一步强调这一结构的重要性，并揭示它在 减数分裂我们的目标是通过利用遗传学的便利来解决这些关键问题， 通过使用线虫C. elegans是种系研究的理想模型系统。我们在上一次融资中取得的进展 新的数据和分子靶点，使我们处于一个理想的位置， 染色体联会的调控以及SC在减数分裂中的作用。这里 我们提出了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（SC的中心区域组分）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。 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， 我们假设它可以作为SC结构成分的分子支架。 并研究了GRAS-1和哺乳动物GRASP之间的功能保守性 和CYTIP蛋白的结合研究。线虫和老鼠这些研究将使 新的光对我们的理解机制调节染色体突触和 SC的作用。我们的研究预计将影响多个领域的巨大相关性， 人类健康，包括染色体动力学，翻译后修饰的研究， 和调节大分子结构。总之，该应用程序将提供 重要的新见解的分子机制调节准确的染色体 减数分裂期间的分离。

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.