Identification and Investigation of Novel DNA Damage Repair Genes Via Network Analysis

Abstract

While most DNA lesions are repaired faithfully and without genotoxic effect, doublestranded breaks (DSBs) are exceptional. The deleterious potential of a misrepaired DSB represents a severe threat to cellular integrity. Repair machinery defects are frequently observed in tumorigenic and oncogenic cells. General DNA damage repair mechanisms involve homologous recombination (HR), or non-homologous end joining (NHEJ).Ongoing identification of new players in DSB repair leads us to believe there are more undiscovered genes in this pathway. The highly complex and conserved nature of DSB repair across eukaryotic and mammalian cells presents an opportunity for identification of novel genes through a computationally-directed approach. Employing a 'guilt-byassociation' model, we analyzed experimental and predicted interaction networks in S. cerevisiae to identify previously uncharacterized genes involved in repair. Three novel genes were discovered to influence repair-GAL7, YHI9, and YMR130W. The results of this study implicate all three in the DNA damage response network.iii