During meiotic prophase, homology recognition between partner chromosomes is coordinated with the assembly of a proteinaceous scaffold, the synaptonemal complex (SC), along the length of the chromosome pair (synapsis). Interhomolog recombination progresses within the context of assembled SC, and many interhomolog recombination events rely on SC for their proper distribution and/or completion. Our lab investigates SC structure and how SC assembly is coordinated with meiotic prophase chromosomal events. Recently we demonstrated that In S. cerevisiae, at least some components of the SC remain dynamic during meiotic prophase, even after chromosomes are fully synapsed. Moreover we found that recombination sites maintain a different SC dynamic as compared to other sites on the SC. Furthermore, our preliminary studies show that SUMO, which localizes to SC structures, has a mutually dependent relationship with the coiled-coil Zip1 protein to assemble SC on meiotic chromosomes. With pioneering imaging studies using super-resolution light microscopy, we have also shown that SUMO localizes to Zip1 N termini, at the center of SC structure. Finally, the lab has isolated zip1 alleles that assemble on chromosomes independent of canonical regulators. Each zip1 allele represents a single amino acid substitution at the extreme C terminus of Zip1 and may reveal aspects of the mechanism underlying Zip1 assembly. The purpose of this grant proposal is to 1) use our established genetic and microscopy tools to define the molecular architecture and dynamics of all known synapsis proteins within the SC, and 2) to isolate point mutant alleles of synapsis initiation proteins and Zip1 in order to identif molecular features of each protein responsible for their function in synapsis and other meiotic prophase chromosomal events.

Public Health Relevance

As SC links the major meiotic chromosomal events of homolog pairing with crossover recombination, this meiotic structure interfaces with signals that determine homology recognition and with crossover-directed recombination machinery. However, little is understood about how the structure is assembled or even what the structure looks like in its assembled form. The purpose of our Proposed Aims is to 1) develop a comprehensive molecular map of a widely conserved meiotic prophase chromosome structure, the synaptonemal complex (SC), in budding yeast;2) continue defining the dynamics of SC proteins during meiotic prophase;and 3) generate mutant alleles of SC proteins that will, together with our new knowledge of SC molecular architecture, reveal insight into the molecular mechanism underlying SC assembly. A detailed understanding of SC structure and its mechanism of assembly will provide fundamental insight into how SC is regulated by checkpoint-like signaling during meiotic prophase and for defining how it influences crossover recombination. As the level and distribution of crossover recombination events impacts meiotic chromosome segregation, disruptions in SC assembly or maintenance that lead to a deficit in crossovers can lead to aneuploidy-associated disorders such as Down's Syndrome. Our proposed studies will uncover fundamental features of how meiotic chromosomes interact with one another and with other cellular signaling pathways in reproductive cells in order to guard against such segregation errors.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15GM104827-01A1
Application #
8575009
Study Section
Molecular Genetics A Study Section (MGA)
Program Officer
Hamlet, Michelle R
Project Start
2013-09-01
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2016-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$372,445
Indirect Cost
$145,483
Name
Wesleyan University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
145683954
City
Middletown
State
CT
Country
United States
Zip Code
06459