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Regulation of crossover recombination in Caenorhabditis elegans

  • Author(s): Lee, Teresa Wei-sy
  • Advisor(s): Meyer, Barbara J
  • et al.
Abstract

Most eukaryotes reproduce sexually, which requires the creation of gametes through a specialized cell division known as meiosis. Crossover recombination is an essential feature of meiosis: in individuals, it facilitates proper chromosome segregation to prevent the formation of aneuploid embryos; within populations of species, it generates novel combination of alleles, to promote genetic diversity and remove deleterious mutations. Crossovers are initiated by programmed double-strand breaks (DSBs), which are a highly toxic form of DNA damage. Meiosis requires a cell to maintain an equilibrium between forming enough DSBs to generate an adequate number of crossovers, but not so many DSBs that some are left unrepaired. Therefore, recombination is subject to strict regulation at all levels, from DSB formation to crossover resolution via a certain mode of DSB repair. In this dissertation, I investigate crossover resolution pathways in the model nematode C. elegans. To ensure the repair of all DSBs formed during meiosis, some organisms have multiple, compensatory repair pathways. Recent studies in C. elegans have identified two parallel pathways with partially overlapping resolvases, XPF-1 and MUS-81. Although XPF-1 and MUS-81 act interchangeably to resolve crossovers in wild-type animals, I show that each becomes required under conditions that threaten chromosome integrity, whether from exposure ionizing radiation or reducing the concentration of condensin, a complex required for proper chromosome structure. Conditions that independently do not create a requirement for a particular resolvase can, when combined, generate a requirement, indicating that these pathways are influenced by factors that act in a combinatorial manner. Although resolvase dependence in irradiated and condensin-depleted animals correlates with the extent of DNA damage, I demonstrate that the absolute number of DSBs is not solely responsible for invoking a requirement. Thus, DSB repair pathway choice may generate different classes of crossover depending on the DSB provenance or cellular reactions to the inducing condition. This work provides insights into the complexity of DSB repair pathways and establishes a framework for the future of pathway interactions, especially under circumstances that stress ordinary repair processes.

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