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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.

项目总结