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In this dissertation I have investigated roles of the 19S proteasome regulatory particle spanning all three types of cell division processes, including meiosis I, meiosis II and mitosis. Utilizing the conditional phenotype of an epitope tagged allele of the essential ATPase Rpt6, I was able to demonstrate that the 19S regulatory particle is required at two steps of homologous recombination, during DSB formation and DSB strand exchange. Under conditions that allow efficient DSB formation to proceed, crossover formation is specifically reduced whereas noncrossovers (i.e. gene conversions not accompanied by an exchange of flanking chromosome arms) occur normally, indicating that the proteasome is required for a distinct subset of DSB repair events. This phenotype is remarkably similar to a mutant carrying an impaired core proteasome, suggesting that the 19S and 20S collaborate as a part of a 26S holo-proteasome.In a second project, I discovered that 19S proteasome defects result in a failure to disjoin sister chromatids during meiosis II, while segregation of sister chromatids during mitosis is unaffected, indicating special demands on the protein quality control system at the second meiotic cell division.Third, although the rpt63HA 19S allele has little or no effect on vegetative growth, when combined with a small subset of polymorphisms from a different wild type yeast strain, it results in a dramatic reduction in growth rate. Specifically, Next Generation Sequencing analysis narrowed down the haplotype responsible for this synergistic effect to ~20 single nucleotide polymorphisms in a genome region occupied by only four genes. This finding suggests how proteasome dysfunction is modulated by genetic background, where it is compatible with the wild type allele from one, but not with that from another strain background. Notably, proteasome disruptions are linked to neurodegenerative disorders like Alzheimer’s and Parkinson’s disease and are also associated with treatments for certain cancers. My identification of natural polymorphisms that enhance the effects of proteasome dysfunction can serve as model for complex diseases where distinct combinations of polymorphisms modulate the penetrance of a disease phenotype.