The p53-like Protein CEP-1 is Required for Meiotic Fidelity in the C. elegans Germline

The production of gametes with the correct genome content relies on the formation of crossovers (CO) during meiosis. This involves the deliberate creation of programmed double strand breaks (DSB) in the DNA and their accurate repair by homologous recombination between paternal and maternal chromosomes. The sites of COs serve as physical connections between homologous chromosomes and allow them to segregate accurately during the first meiotic division. Thus, in addition to generating genetic diversity, COs are critical for maintaining genome stability. Multiple studies have hinted at a role for the p53 family in meiosis, but the mechanism behind this is poorly understood. Here, I describe novel roles for the p53-like protein CEP-1 in ensuring meiotic fidelity in the C. elegans germline. I show that CEP-1 collaborates with the meiotic protein HIM-5 to regulate the formation and accurate repair of SPO-11-dependent DSBs. In addition, using a cep-1 separation-of-function allele, I demonstrate that cep-1 and him-5 suppress erroneous nonhomologous end-joining activity to commit DNA repair to HR. Furthermore, I also detail the novel roles I uncovered for the C. elegans homolog for the breast cancer susceptibility gene 1, BRC-1, in maintaining genome stability. Like CEP-1, BRC-1 collaborates with HIM-5 during physiological conditions to promote the creation and accurate repair of meiotic DSBs. On the other hand, BRC-1 cooperates with CEP-1 to safeguard genetic information following exposure to ionizing radiation. Together, CEP-1, HIM-5 and BRC-1 form multifunctional hubs that coordinate distinct, but interconnected, pathways to maintain genome integrity in the C. elegans germline.Ph.D