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?

Public Health Relevance

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

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Transition Award (R00)
Project #
5R00GM084293-05
Application #
8133848
Study Section
Special Emphasis Panel (NSS)
Program Officer
Janes, Daniel E
Project Start
2008-04-01
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$244,044
Indirect Cost
Name
Wesleyan University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
145683954
City
Middletown
State
CT
Country
United States
Zip Code
06459
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; Lefran├žois, 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