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 have identified at least three molecular pathways that regulate synapsis. The Fpr3 and Rrdl proteins independently promote the formation of poly complex 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. The Fpr3 and Rrdl proteins each have proline isomerase activity, raising the possibility that the capacity of Zip 1 to assemble SC is under regulation by chaperone proteins in the nucleus. Zip3, on the other hand, plays a role in preventing SC assembly on chromosomes. When polycomplex formation is compromised and Zip3 activity is missing, (as in a zip3 fpr3 double mutant), SC components polymerize on chromosomes, independent of homolog alignment. Interestingly, the linear SC structures that arise in zip3 fpr3 nuclei originate from centromere regions. This suggests a role for centromeres in coordinating major meiotic chromosomal events and draws an interesting parallel between yeast centromeres and C. elegans Pairing Centers. As Zip3 colocalizes with the SC structural component, Zipl, at centromere regions prior to homolog alignment, perhaps Zip3 contributes to reinforcing homolog recognition by regulating SC assembly at centromeres. The experiments proposed use genetic, cytological and biochemical approaches to ask: How do Fpr3, Rrdl and Zip3 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.@ga
|Voelkel-Meiman, Karen; Johnston, Cassandra; Thappeta, Yashna et al. (2015) Separable Crossover-Promoting and Crossover-Constraining Aspects of Zip1 Activity during Budding Yeast Meiosis. PLoS Genet 11:e1005335|
|Voelkel-Meiman, Karen; Taylor, Louis F; Mukherjee, Pritam et al. (2013) SUMO localizes to the central element of synaptonemal complex and is required for the full synapsis of meiotic chromosomes in budding yeast. PLoS Genet 9:e1003837|
|Voelkel-Meiman, Karen; Moustafa, Sarah S; Lefrançois, Philippe et al. (2012) Full-length synaptonemal complex grows continuously during meiotic prophase in budding yeast. PLoS Genet 8:e1002993|
|MacQueen, Amy J; Hochwagen, Andreas (2011) Checkpoint mechanisms: the puppet masters of meiotic prophase. Trends Cell Biol 21:393-400|