权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Control of pairing and recombination during meiosis

减数分裂过程中配对和重组的控制

基本信息

批准号：
8180448
负责人：
Valentin Boerner
金额：
$ 28.4万
依托单位：
CLEVELAND STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-16 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8180448
关键词：
Alleles Aneuploidy Animal Model Attention Cells Chromosome Pairing Chromosome Segregation Chromosome Structures Chromosomes Congenital Abnormality DNA Defect Elements Event Exhibits Failure Future Genetic Recombination Genetic Screening Germ Cells Goals Homologous Gene Human Infertility Intervention Malignant Neoplasms Mediating Medical Meiosis Meiotic Prophase I Meiotic Recombination Molecular Optic Chiasm Organism Pathway interactions Play Positioning Attribute Predisposition Pregnancy Prevention Process Proteins Proteolysis Reproductive Health Research Role Saccharomycetales Sequence Homologs Series Sister Chromatid Staging Synaptonemal Complex Therapeutic Intervention Ubiquitin-mediated Proteolysis Pathway gene induction genetic regulatory protein genome wide association study innovation insight multicatalytic endopeptidase complex mutant polymerization programs protein degradation protein structure reproductive segregation

项目摘要

DESCRIPTION (provided by applicant): Accurate chromosome segregation during meiosis is essential for normal gamete formation in sexually reproducing organisms. Meiotic defects result in reproductive failure and birth defects. Prior to their segregation during meiosis I, homologous chromosomes undergo recombination and close juxtaposition via the synaptonemal complex. Together, these events culminate in the formation of chiasmata/crossovers, physical connections that mediate bipolar attachment of homologs to the meiosis I spindle. Two spatially and temporally integrated pathways contribute to chiasma formation. On the DNA level, homologous sequences undergo pairing, followed by double strand break formation and processing of a non-random subset of double strand breaks into crossovers. At the level of higher order chromosome structure, continuous protein axes form along sister chromatids which become juxtaposed with their homologous partner via the central element of the synaptonemal complex. The function of the synaptonemal complex and the coordination of transitions in chromosome structure and recombination are currently not understood. Our long term goal is to clarify the role in recombination and chromosome segregation of the synaptonemal complex. Our own preliminary findings define early and late recombination functions of the synaptonemal complex component Zip1. A particular Zip1 allele separates functions in recombination from those in SC polymerization. A genome-wide screen has further identified functions in synaptonemal complex formation and recombination of a component of the core proteasome, the machinery that mediates degradation of many proteins. These findings identify proteolysis as an important control mechanism of meiosis. The current proposal aims to dissect early and late functions of the synaptonemal complex by identifying specialized mutant conditions that define SC functions at early and late steps of recombination. As a second aim, the role of proteasome-mediated destruction of regulatory proteins during meiosis will be investigated. Together, our approach will provide a mechanistic understanding of factors with key roles in reproductive health. PUBLIC HEALTH RELEVANCE: Up to 30% of clinically recognized human pregnancies exhibit aneuploidies, i.e. a deficit or surplus of one or several chromosomes. Most chromosomal imbalances result from chromosome missegregation during meiosis. Meiotic mistakes thus are the leading cause of infertility and birth defects in humans. A mechanistic understanding of meiotic mechanisms of chromosome segregation is essential to make this problem accessible to future medical intervention.

描述（由申请人提供）：减数分裂期间准确的染色体分离对于有性生殖生物体的正常配子形成至关重要。减数分裂缺陷导致生殖失败和出生缺陷。在减数分裂I期间分离之前，同源染色体通过联会复合体进行重组和紧密并置。总之，这些事件最终形成交叉/交叉，介导同源物与减数分裂I纺锤体的双极连接的物理连接。两个空间和时间整合的途径有助于交叉的形成。在DNA水平上，同源序列进行配对，然后形成双链断裂并将双链断裂的非随机子集加工成交叉。在高级染色体结构水平上，连续的蛋白质轴沿着沿着姐妹染色单体形成，这些姐妹染色单体通过联会复合体的中心元件与它们的同源配偶体并置。联会复合体的功能和染色体结构和重组中的过渡协调目前还不清楚。我们的长期目标是阐明联会复合体在重组和染色体分离中的作用。我们自己的初步研究结果定义了联会复合体组件Zip 1的早期和晚期重组功能。一个特殊的Zip 1等位基因将重组中的功能与SC聚合中的功能分开。一个全基因组的屏幕已进一步确定功能联会复合体的形成和重组的核心蛋白酶体的一个组成部分，介导许多蛋白质的降解的机器。这些发现表明蛋白水解是减数分裂的重要控制机制。目前的建议旨在解剖联会复合体的早期和晚期功能，通过识别在重组的早期和晚期步骤定义SC功能的专门的突变条件。作为第二个目标，在减数分裂过程中的调节蛋白的蛋白酶体介导的破坏的作用将进行调查。总之，我们的方法将提供一个机制的理解与生殖健康的关键作用的因素。公共卫生相关性：高达30%的临床确认的人类妊娠表现出非整倍性，即一个或多个染色体的缺陷或过剩。大多数染色体不平衡是由减数分裂时染色体的错误分离引起的。因此，减数分裂错误是人类不育和出生缺陷的主要原因。染色体分离的减数分裂机制的机械理解是必不可少的，使这个问题可以在未来的医疗干预。