Thursday, May 2, 2024
5/2/2024
RESEARCH SUMMARY Recombination between chromosomes is required to generate genetic variation, maintain genome integrity, and ensure proper chromosome segregation during meiosis, the specialized cell division program that generates haploid gametes such as sperm and eggs. Perturbations in recombination can compromise these basic cellular functions, ultimately leading to cancer, infertility, or birth defects. Meiotic recombination is initiated by programmed double strand DNA breaks (DSBs), which are repaired using meiosis-specific mechanisms that 1) favor utilization of the homologous chromosome (instead of the sister chromatid) as the repair partner; and, 2) promote a crossover outcome of the DSB repair process, which is required for proper chromosome segregation during meiosis. Although repair of DSBs with the appropriate template (homologous chromosome) is necessary for proper chromosome segregation and genome integrity, our knowledge of how germ cells achieve this critical template preference in the presence of nearly identical sequences (sister chromatids) is limited due to assay limitations in metazoans. The goal of our research program is to understand how chromosomes are able to access distinct recombination pathways and partners to ensure faithful genome inheritance. Using in vivo assays we developed in the model system Caenorhabditis elegans, we have directly detected and analyzed use of the sister chromatid as a repair template during metazoan meiotic prophase I progression. Building upon our published work, we are defining and establishing how specific chromosome structures, proteins, and cellular contexts regulate recombination pathway and repair partner choices to maintain meiotic genome integrity. Using our in vivo assay along with a combination of genetic, cytological, and sequencing based approaches, we will test models of how particular meiotic chromosome structures regulate and respond to specific repair pathway and partner choices. We will also determine how the NSE-2/Mms21 E3 SUMO ligase regulates repair pathway choices and genomic stability during oogenesis. Using whole genome sequencing, we will define recombination landscape with its molecular signatures to determine how chromosomal context, sex, and age affect crossover and noncrossover numbers and distribution across the genome. Finally, we will induce and analyze single DSBs in specific genomic locations to determine how specific chromosome features affect what pathways and partners are used to repair a DSB. Overall, these studies will reveal how recombination pathway and partner choices ensure that chromosomes form the connections necessary for chromosome segregation and repair DSBs for maintaining genomic integrity during sperm and egg development.
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