Control of pairing and recombination during meiosis

描述（由申请人提供）：在有性生殖生物中，减数分裂过程中准确的染色体分离对于正常配子的形成至关重要。减数分裂缺陷导致生殖失败和出生缺陷。同源染色体在减数分裂I期间分离之前，通过突触复合体进行重组和紧密并列。总之，这些事件在交叉/交叉的形成中达到高潮，物理连接介导了减数分裂I纺锤体同源物的双极性附着。两个空间和时间上整合的路径有助于交错的形成。在DNA水平上，同源序列进行配对，随后形成双链断裂，并将双链断裂的非随机子集加工成交叉。在高阶染色体结构的水平上，连续的蛋白质轴沿着姐妹染色单体形成，这些染色单体通过突触复合体的中心元件与同源染色单体并列。突触复合体的功能以及染色体结构和重组过渡的协调目前尚不清楚。我们的长期目标是阐明突触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定义了突触复合体成分Zip1的早期和晚期重组功能。一个特殊的Zip1等位基因将重组中的功能与SC聚合中的功能分开。全基因组筛选进一步确定了突触复合物形成和核心蛋白酶体组分重组的功能，核心蛋白酶体是介导许多蛋白质降解的机制。这些发现表明蛋白质水解是减数分裂的重要控制机制。目前的建议旨在通过确定在重组的早期和后期步骤中定义SC功能的专门突变条件来解剖突触复合物的早期和晚期功能。作为第二个目标，将研究减数分裂过程中蛋白酶体介导的调节蛋白破坏的作用。总之，我们的方法将提供对在生殖健康中起关键作用的因素的机械理解。

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.