Control of pairing and recombination during meiosis

描述(由申请人提供)：减数分裂过程中准确的染色体分离对于有性生殖生物体中正常的配子形成是必不可少的。减数分裂缺陷会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列。总而言之，这些事件最终形成了交叉/交叉，这是一种物理连接，介导了同系物与减数分裂I纺锤体的两极连接。两条时空整合的通路有助于交叉的形成。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处理成交叉。在高阶染色体结构水平上，连续的蛋白质轴沿着姐妹染色单体形成，这些染色单体通过联会复合体的中心元件与其同源伙伴并列。联会复合体的功能以及染色体结构和重组中过渡的协调目前尚不清楚。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。我们自己的初步发现确定了联会复合体成分ZIP1的早期和晚期重组功能。一个特定的ZIP1等位基因将重组功能与SC聚合功能分开。全基因组筛查进一步确定了核心蛋白酶体的一个组成部分的联会复合体形成和重组的功能，核心蛋白酶体是调节许多蛋白质降解的机制。这些发现表明，蛋白质分解是减数分裂的重要控制机制。目前的建议旨在通过确定特定的突变条件来剖析联会复合体的早期和晚期功能，这些突变条件定义了重组早期和晚期的SC功能。作为第二个目标，我们将研究蛋白酶体在减数分裂过程中对调节蛋白的破坏作用。总之，我们的方法将提供对生殖健康中具有关键作用的因素的机械性理解。 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体，即一个或几个染色体的缺失或过剩。大多数染色体不平衡是由减数分裂过程中的染色体错误分离引起的。因此，减数分裂错误是人类不孕不育和出生缺陷的主要原因。从机制上理解染色体分离的减数分裂机制对于使这一问题成为未来医学干预的基础是至关重要的。

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.