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，染色体开始广泛的重组，最终形成对齐的同源染色体，通过突触复合体（SC）沿其长度连接，并且每个染色体都能够与其伴侣进行重组。这一过程对于有性生殖生物配子形成过程中精确的染色体分离至关重要。尽管一个多世纪以来，人们在多种生物中观察到减数分裂染色体配对和突触，但减数分裂染色体基本事件的分子机制仍然未知。同源染色体如何相互识别？这种最初的认识是如何加强的？同源识别是如何与SC组装协调的，从而使配对染色体之间特异性地发生突触？我已经开始通过筛选调节芽殖酵母中SC组装的因子来研究这些问题。我确定了两个因素在SC调节中的作用。FPR3基因促进细胞核中同源比对缺陷的多复合物的形成。多络合物是SC组分的局部聚集，反映了染色体上SC聚合的失败，经常发生在配对或重组中有早期减数分裂缺陷的突变体中。另一方面，ZIPS在阻止SC在染色体上的组装中起作用。当多复合体形成受损，ZIPS活性缺失时（如ZIPS fprS双突变），SC成分在染色体上聚合，与同源比对无关。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。由于在同源比对之前，zip与SC结构成分Zip1在着丝粒区域共定位，可能zip通过调节SC在着丝粒的组装来加强同源识别。实验建议使用遗传学，细胞学和蛋白质组学方法来问：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？提出的研究旨在了解控制减数分裂染色体过程的基本细胞机制，这在酵母和哺乳动物之间是保守的。由于减数分裂染色体分离缺陷导致不育和唐氏综合症等疾病，希望我的研究成果可以在理解、治疗和培育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.