Meiosis is a specialized form of cell division that leads to the production of two distinct gamete types, sperm and egg, for sexual reproduction. In addition to a haploid set of chromosomes, sperm and egg must provide the embryo with unique but complementary products to support development. To accomplish this, the meiotic program is sexual dimorphic; however, the mechanisms underlying differences in male and female meiosis have remained elusive. We have identified sex-specific roles for the tumor suppressor E3 ubiquitin ligase BRCA1/BARD1 complex in meiotic recombination, and in checkpoint signaling, and thus are uniquely positioned to determine the underlying molecular mechanisms regulating meiosis in the sexes. Our overall hypothesis is that sex-specific differences in recombination and checkpoint signaling serve to balance the accurate transmission of the genome with overall reproductive success. To test this hypothesis, we propose to elucidate conserved mechanisms underlying chromosome behavior during male and female meiosis using the simple metazoan animal model Caenorhabditis elegans, which overcomes many technical challenges inherent in mammalian systems.
In Aim 1 we will determine mechanistically how BRCA1/BARD1 mediates double-strand break processing in male versus female germ cells, using targeted genetic, cell biological and biochemical approaches. We will also determine the significance of E3 ubiquitin ligase activity to BRCA1/BARD1 function in meiosis.
In Aim 2 we will elucidate mechanisms underlying how BRCA1/BARD1 is regulated to perform the sex-specific functions defined in Aim 1.
In Aim 3 we will uncover the role of BRCA1/BARD1 in checkpoint signaling under conditions where there are errors in recombination and chromosome alignment to determine mechanisms underlying the fidelity of male meiosis. Together, an understanding of these processes in the genetically tractable C. elegans system will provide novel and important insights into how the meiotic program is regulated in a sex-specific manner. These studies have direct relevance to understanding the increased frequency of errors associated with human meiosis resulting in developmental disorders such as Down?s Syndrome. Importantly, these studies will also elucidate general mechanisms of, and the involvement of BRCA1/BARD1 in, DNA repair, chromosome segregation and checkpoint signaling, events that play critical roles in maintaining genome integrity in all cells.
Our studies are aimed at understanding how meiosis is regulated in males and females, to ensure formation of sperm and egg with the correct number of chromosomes and cellular components to support development. The work is highly relevant to human health as errors in meiosis result in infertility, spontaneous abortion, and birth defects. These studies will also provide insight into how genome integrity is compromised in diseases such as cancer.
