Identification and characterization of dosage mutator genes in Saccharomyces cerevisiae

Cancer is due to an accumulation of mutations in constellations of genes that cause uncontrolled proliferation and evasion of apoptotic pathways. In addition, mutations that cause genome instability, another hallmark of cancer, predispose cancer progenitor cells to accumulating the large number of mutations and chromosome aberrations that are observed in cancer cells. Genome instability is either due to mutations that cause an increased mutation rate (mutator phenotype) or increases in aberrations to chromosome number or structure (chromosome instability). Recent work has cataloged nearly all genes in the budding yeast, Saccharomyces cerevisiae, that cause a chromosome instability (CIN) phenotype due to reduction-of-function mutations and gain-of-function mutations, with the ultimate goal of translating the results found in yeast to human cancer. To investigate the effects of gene dosage on mutation rate, we systematically overexpressed ~85% of the yeast genome in a CAN1 forward-mutation screen and identified 5 genes that when overexpressed conferred a strong mutator phenotype, several of which have been associated with cancer. Overexpression of MPH1, the yeast ortholog of Fanconi Anemia gene FANCM, resulted in the strongest mutator phenotype. MPH1 was further investigated to gain insight into the mechanisms which lead to its dosage mutator phenotype.Medicine, Faculty ofMedical Genetics, Department ofGraduat