Regulation of Synaptonemal Complex Assembly During Meiosis in S. cerevisiae

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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.