Friday, May 3, 2024
5/3/2024
PROJECT SUMMARY Meiosis is a specialized form of cell division that results in the formation of gametes. Meiotic recombination is a crucial step in this process during which homologous chromosomes physically interact and exchange genetic information. The final recombination DNA intermediate in this process is the double Holliday Junction (dHJ). A major question in the meiosis field is the mechanism through which dHJs are resolved in a biased manner to create crossover products between homologs. Mlh1-Mlh3, the nuclease responsible for resolving the majority of dHJs in budding yeast, does not appear to be intrinsically capable of recognizing and cleaving dHJs in a biased manner. This observation combined with genetic screens revealing a wide variety of crossover promoting factors indicates that other proteins may interact at the dHJ to promote biased resolution. Here I aim to interrogate Exo1, a crossover promoting factor with well-established roles as a nuclease in homology directed repair (HDR) and mismatch repair (MMR). Interestingly, despite playing an important role in crossover formation previous work shows that catalytically deficient exo1 mutants do not suffer reductions in crossover frequencies, suggesting a meiotic role for Exo1 that is independent of its nuclease activity. Here, I will investigate the mechanism through which Exo1 promotes the formation of crossovers. I hypothesize that Exo1 acts as a scaffold at the dHJ to stabilize and orient Mlh1-Mlh3 through direct interaction with both the DNA and Mlh1. Additionally, I will follow up on my recent work indicating a pro-CO activity of Exo1 independent of Mlh1 Mlh3 functions that acts upstream of resolution. This work will provide insight into long-standing questions in the meiosis field and open up exciting new paths for future research.
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