title: Shared genetic pathways contribute to the tolerance of endogenous and low-dose exogenous DNA damage in yeast.
abstract: DNA damage that escapes repair and blocks replicative DNA polymerases is tolerated by bypass mechanisms that fall into two general categories: error-free template switching and error-prone translesion synthesis. Prior studies of DNA damage responses in Saccharomyces cerevisiae have demonstrated that repair mechanisms are critical for survival when a single, high dose of DNA damage is delivered, while bypass/tolerance mechanisms are more important for survival when the damage level is low and continuous (acute and chronic damage, respectively). In the current study, epistatic interactions between DNA-damage tolerance genes were examined and compared when haploid yeast cells were exposed to either chronic ultraviolet light or chronic methyl methanesulfonate. Results demonstrate that genes assigned to error-free and error-prone bypass pathways similarly promote survival in the presence of each type of chronic damage. In addition to using defined sources of chronic damage, rates of spontaneous mutations generated by the Pol ζ translesion synthesis DNA polymerase (complex insertions in a frameshift-reversion assay) were used to infer epistatic interactions between the same genes. Similar epistatic interactions were observed in analyses of spontaneous mutation rates, suggesting that chronic DNA-damage responses accurately reflect those used to tolerate spontaneous lesions. These results have important implications when considering what constitutes a safe and acceptable level of exogenous DNA damage.
authors: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710.
authors: Kevin
authors: K
authors: Lehner
authors: Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710 sue.robertson@duke.edu.
authors: Sue
authors: S
authors: Jinks-Robertson
mesh_terms: D001483:Base Sequence; D053487:DEAD-box RNA Helicases / Q000502:physiology; D004249:DNA Damage; D004265:DNA Helicases / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004843:Epistasis, Genetic; D005800:Genes, Fungal; D008969:Molecular Sequence Data; D059767:Recombinational DNA Repair; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; C112520:MMS2 protein, S cerevisiae; C063607:RAD18 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D044767:Ubiquitin-Protein Ligases; C425929:DNA polymerase zeta; D004259:DNA-Directed DNA Polymerase; C491240:MPH1 protein, S cerevisiae; C076225:RAD5 protein, S cerevisiae; D004265:DNA Helicases; D053487:DEAD-box RNA Helicases
keywords: DNA damage; lesion bypass; template switch; translesion synthesis; yeast