Synaptonemal complex assembly and function in meiosis

减数分裂中的联会复合体组装和功能

基本信息

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
项目类别：
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

项目摘要

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，了解其背后的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。这联会复合体（SC）是一种类似拉链的结构，在从酵母到人类的减数分裂过程中普遍存在它在同源染色体之间组装，稳定同源配对相互作用，促进同源物间交叉的形成。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，调节染色体突触的机制并不在任何有机体中都可以很好地理解。此外，研究重点是蛋白质的翻译后调控形成这种结构揭示了 SC 的新作用，将其与 DSB 形成的调节联系起来，交叉指定。这些最近的发现进一步强调了这种结构和揭示它在减数分裂过程中所扮演的角色。我们的目标是通过利用使用线虫可以轻松进行遗传、细胞学、分子和生化分析线虫，种系研究的理想模型系统。我们在上一个资助期间取得的进展，加上有了新的数据和分子靶点，使我们处于了解染色体调控的理想位置联会和 SC 在减数分裂过程中发挥的作用。在这里，我们提出两个综合目标来解决这些问题关键问题。目标 1 将解决 ATM/ATR 介导的中心区域 SYP-4 的磷酸化过程 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 组装有关，我们假设可以作为 SC 结构成分的分子支架。我们还将调查功能通过联合研究，GRAS-1 与哺乳动物 GRASP 和 CYTIP 蛋白共享保守性在线虫和小鼠中。这些研究将为我们理解调节机制提供新的线索染色体突触和 SC 的作用。我们的研究预计将影响多个领域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，以及大分子结构的调控。总而言之，该应用程序将提供重要的新见解减数分裂过程中调节精确染色体分离的分子机制。