Molecular Control of Meiotic Chromosome Dynamics

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Project Summary/Abstract Sexually reproducing organisms rely on meiosis, a specialized cell division that produces haploid gametes such as sperm and eggs, to restore the genetic content of the zygote through fertilization. Errors in this process lead to the production of offspring with an abnormal number of chromosomes or aneuploidy, and this is a major cause of human miscarriages and birth defects such as Down syndrome. Accurate segregation of chromosomes during meiosis requires that they pair, synapse, and undergo crossover recombination with their homologs. Although genetic studies over the decades have identified a list of proteins that are essential for meiotic processes, it remains largely unknown how these protein machines work together to drive and coordinate chromosome dynamics. Our research program will investigate these fundamental processes by combining biochemical analysis using purified components, with the ability to examine meiosis in the context of highly tractable C. elegans germline. One major focus of our work is the synaptonemal complex (SC), a proteinaceous scaffold that assembles between paired homologous chromosomes. The SC is a hallmark of meiotic prophase and yet plays a poorly understood role in regulating crossover recombination. Although genetic and cytological studies have identified SC proteins in various organism, how individual components interact with each other to form the regular, repetitive arrangement of the SC is largely unknown. The recent discovery of two novel SC components in C. elegans, SYP-5 and SYP-6, has uniquely positioned our group to investigate the structure and functions of the SC. We will refine our purification protocols to isolate SYP protein complexes and determine the stoichiometry and protein-protein interactions among the SC components. This work will reveal the molecular map of the SC, which will provide a foundation for understanding its conserved structure throughout eukaryotes. In parallel, we will delineate the signaling cascades by key cell cycle kinases and phosphatases to establish key regulatory mechanisms that govern homolog pairing, synapsis, and meiotic recombination. We will determine the mechanisms by which PLK-2 regulates the dynamic properties of the SC and its affinity to pro-crossover factors. We will also decipher how the CDK multisite phosphorylation code elicits a switch-like response and mediates crossover designation. Our studies will illuminate the mechanisms underlying meiotic chromosome behavior to a biochemical level and ultimately shed light into how organisms faithfully transmit genetic information from parent to progeny.