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: 10459444
• 负责人: Monica P Colaiacovo
• 金额: $ 39.92万
• 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/10459444
• 关键词: Address; Antibodies; Biochemical; Biochemical Process; Biological Assay; Biological Models; Biology; CRISPR/Cas technology; Caenorhabditis elegans; Cell division; Chromosome Pairing; Chromosome Segregation; Chromosomes; Collaborations; Congenital Abnormality; Coupled; Cytology; DNA Damage; DNA Double Strand Break; DNA biosynthesis; Data; Development; Diploidy; Double Strand Break Repair; Down Syndrome; Engineering; Ensure; Event; Failure; Foundations; Frequencies; Funding; Gene Expression; Genes; Genetic; Genetic Nondisjunction; Genetic Recombination; Genome; Germ Cells; Goals; Haploidy; Health; Homologous Gene; Human; Image; In Vitro; Infertility; Jordan; Laboratories; Lead; Light; Link; Mediating; Meiosis; Mitosis; Molecular; Molecular Structure; Molecular Target; Monitor; Mus; Nematoda; Organism; Pathway interactions; Phenotype; Phosphopeptides; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Positioning Attribute; Post-Translational Protein Processing; Post-Translational Regulation; Prevention strategy; Process; Protein Analysis; Proteins; Regulation; Regulatory Pathway; Reproductive Health; Resolution; Role; Series; Signal Transduction; Site; Spontaneous abortion; Structure; Synaptonemal Complex; System; Testing; Universities; Work; Yeasts; egg; genome editing; in vivo; insight; mutant; novel; programs; repaired; response; scaffold; spatiotemporal; sperm cell; stillbirth; yeast two hybrid system

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 减数分裂过程中未能实现准确的染色体分离是流产的主要原因， 不孕症和出生缺陷，例如唐氏综合症。因此，了解基本机制 减数分裂过程中准确的染色体分离对人类健康至关重要。这 突发型复合物（SC）是一种拉链状结构，从酵母到人的减数分裂过程中存在普遍存在 它在同源染色体之间稳定同源配对相互作用和 促进本体间跨界形成。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，调节染色体突触的机制不是 在任何有机体中都了解。此外，研究侧重于蛋白质的翻译后调节 形成这种结构正在揭示SC的新作用，将其与DSB形成的调节联系起来 跨界名称。这些最新发现进一步强调了这种结构和 揭示其在减数分裂过程中所扮演的角色。我们的目标是通过利用 通过使用线虫提供的遗传，细胞学，分子和生化分析的易度性 秀丽隐杆线虫，一种用于种系研究的理想模型系统。我们在上一个资金期间的进展，耦合 有了新的数据和分子靶标，我们将我们处于了解染色体调节的理想位置 SC在减数分裂过程中扮演的突触和角色。在这里，我们提出了两个综合目的来解决这些问题 关键问题。 AIM 1将解决AMT/ATR介导的SYP-4的磷酸化（中央区域） 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，我们假设 可以充当SC的结构成分的分子支架。我们还将研究功能 通过合并研究 在秀丽隐杆线虫和小鼠中。这些研究将为我们对调节机制的理解提供新的启示 染色体突触和SC的作用。我们的研究有望影响多个巨大的领域 与人类健康的相关性，包括染色体动态，翻译后修饰的研究以及 大分子结构的调节。综上所述，此应用程序将为您提供重要的新见解 减数分裂过程中调节准确的染色体分离的分子机制。