Author Description

The genetic information required for life is stored within molecules of DNA. This DNA is under constant attack as a result of normal cellular metabolic processes, as well as exposure to genotoxic agents. DNA damage left unrepaired can result in mutations that alter the genetic information encoded within DNA. Cells have consequently evolved complex pathways to combat damage to their DNA. Defects in the cellular response to DNA damage can result in genomic instability, a hallmark of cancer cells. Identifying all the components required for this response remains an important step in fully elucidating the molecular mechanisms involved. I used functional genomic approaches to identify genes required for the DNA damage response in Saccharomyces cerevisiae. I conducted a screen to identify genes required for resistance to a DNA damaging agent, methyl methanesulfonate, and identified several poorly characterized genes that are necessary for proper S phase progression in the presence of DNA damage. Among the genes identified, ESC4/RTT107 has since been shown to be essential for the resumption of DNA replication after DNA damage. Using genome-wide genetic interaction screens to identify genes that are required for viability in the absence of MUS81 and MMS4, two genes required for resistance to DNA damage, I helped identify ELG1, deletion of which causes DNA replication defects, genomic instability, and an inability to properly recover from DNA damage during S phase. I also used two-dimensional hierarchical clustering of synthetic genetic interaction data determined by large-scale genetic network analysis to identify RMI1, which encodes a new member of the highly conserved Sgs1-Top3 complex that is an important suppressor of genomic instability.