Regulation of Synaptonemal Complex Assembly During Meiosis in S. cerevisiae

描述（由申请人提供）：在减数分裂开始时，染色体开始广泛重组，最终形成对齐的同源染色体，通过联会复合体（SC）沿着其长度连接，并且每个染色体都能够与其配偶体重组。这一过程对于有性生殖生物配子形成过程中染色体的准确分离至关重要。尽管世纪来对不同生物体中减数分裂染色体配对和联会的观察，但基本减数分裂染色体事件的分子机制仍然未知。同源染色体如何相互识别？这种初步认识是如何得到加强的？同源物识别是如何与SC组装协调的，使得突触特异性地发生在成对的染色体之间？我已经开始调查这些问题，通过筛选因子，调节SC组装芽殖酵母。我确定了两个因素在SC调节中的作用。FPR3基因促进同源物比对缺陷的细胞核中多复合物的形成。多复合物是SC组分的焦点积累，反映了染色体上SC聚合的失败，并且经常发生在配对或重组中具有早期减数分裂缺陷的突变体中。另一方面，ZIPS在防止SC在染色体上组装中起作用。当多复合物形成受到损害并且ZIPS活性缺失时（如在zipS fprS双突变体中），SC组分在染色体上重叠，独立于同源物比对。有趣的是，在zipS fprS核中出现的线性SC结构起源于着丝粒区域。由于ZipS在同源物比对之前与SC结构组分Zip 1共定位在着丝粒区域，因此ZipS可能通过调节SC在着丝粒的组装来有助于加强同源物识别。提出的实验使用遗传学，细胞学和蛋白质组学的方法来问：FPRS和ZIPS如何调节SC组装？SC组装、重组和同源配对之间的分子关系是什么？拟议的研究旨在了解控制酵母和哺乳动物之间保守的减数分裂染色体过程的基本细胞机制。由于减数分裂染色体分离缺陷会导致不育和唐氏综合症等疾病，因此希望从我的研究中学到的东西可以在理解，治疗和培养人类生殖健康方面发挥作用。

DESCRIPTION (provided by applicant): At the start of meiosis, chromosomes initiate an extensive reorganization that culminates in aligned homologous chromosomes, joined along their lengths by synaptonemal complex (SC), and each capable of undergoing recombination with its partner. This process is critical for accurate chromosome segregation during gamete formation in sexually reproducing organisms. Despite over a century of observing meiotic chromosome pairing and synapsis in diverse organisms, the molecular mechanisms underlying fundamental meiotic chromosomal events are still unknown. How do homologous chromosomes identify one another? How is this initial recognition reinforced? How is homolog recognition coordinated with SC assembly, such that synapsis occurs specifically between paired chromosomes? I have begun to investigate these questions by screening for factors that regulate SC assembly in budding yeast. I identified roles for two factors in SC regulation. The FPR3 gene promotes the formation of polycomplexes in nuclei that are defective in homolog alignment. Polycomplexes are focal accumulations of SC components that reflect a failure in SC polymerization on chromosomes, and frequently occur in mutants with early meiotic defects in pairing or recombination. ZIPS, on the other hand, plays a role in preventing SC assembly on chromosomes. When polycomplex formation is compromised and ZIPS activity is missing, (as in a zipS fprS double mutant), SC components polymerize on chromosomes, independent of homolog alignment. Interestingly, the linear SC structures that arise in zipS fprS nuclei originate from centromere regions. As ZipS colocalizes with the SC structural component, Zip1, at centromere regions prior to homolog alignment, perhaps ZipS contributes to reinforcing homolog recognition by regulating SC assembly at centromeres. The experiments proposed use genetic, cytological and proteomic approaches to ask: How do FPRS and ZIPS regulate SC assembly? What is the molecular relationship between SC assembly, recombination and homolog pairing? The proposed research aims to understand basic cellular mechanisms that control meiotic chromosome processes that are conserved between yeast and mammals. As meiotic chromosome segregation defects lead to infertility and disorders such as Down's Syndrome, it is hoped that what is learned from my research may play a role in understanding, treating, and nurturing human reproductive health.