The control of crossing over in fission yeast

Genome stability is essential for fitness and survival of organisms. There exist many repair mechanisms to ensure the integrity of DNA. A major DNA repair mechanism is homologous recombination (HR), which can repair double strand breaks (DSBs) and damaged replication forks. However, HR is a double-edged sword in that it can also promote genome instability, since in mitotic cells the generation of crossover (CO) recombinants can result in deleterious genome rearrangements. In meiosis, however, CO exchange between homologous chromosomes generates chiasmata which are essential for faithful segregation. A critical factor for genome stability in fungi and mammals is the XPF-related endonuclease Mus81. It forms a heteromeric complex with Eme1/Mms4 (referred to as the Mus81 complex herein), and is active in both vegetative and generative cells. In generative cells it functions during DSB repair to generate CO recombinants, whereas in vegetative cells it is limited to the repair of damaged replication forks, and seems to play no role in DSB repair. Mus81 complexes cleave a wide range of different DNA junction structures in vitro, suggesting that Mus81 functions in various ways to promote repair of DSBs and damaged replication forks. In addition to Mus81 there are a number of DNA helicases that direct the manner in which recombination intermediates are processed. Here I propose a detailed study of how the Mus81 complex works and is regulated in mitotic and meiotic cells in the fission yeast Schizosaccharomyces pombe. This will be linked to the wider aim of determining which proteins are important for controlling CO formation in mitotic and meiotic cells. These studies are expected to lead to a better understanding of how genomes are maintained, and in particular how Mus81-Eme1 prevents tumourigenesis in mammals.