title: Defects in base excision repair sensitize cells to manganese in S. cerevisiae.
abstract: Manganese (Mn) is essential for normal physiologic functioning; therefore, deficiencies and excess intake of manganese can result in disease. In humans, prolonged exposure to manganese causes neurotoxicity characterized by Parkinson-like symptoms. Mn(2+) has been shown to mediate DNA damage possibly through the generation of reactive oxygen species. In a recent publication, we showed that Mn induced oxidative DNA damage and caused lesions in thymines. This study further investigates the mechanisms by which cells process Mn(2+)-mediated DNA damage using the yeast S. cerevisiae. The strains most sensitive to Mn(2+) were those defective in base excision repair, glutathione synthesis, and superoxide dismutase mutants. Mn(2+) caused a dose-dependent increase in the accumulation of mutations using the CAN1 and lys2-10A mutator assays. The spectrum of CAN1 mutants indicates that exposure to Mn results in accumulation of base substitutions and frameshift mutations. The sensitivity of cells to Mn(2+) as well as its mutagenic effect was reduced by N-acetylcysteine, glutathione, and Mg(2+). These data suggest that Mn(2+) causes oxidative DNA damage that requires base excision repair for processing and that Mn interferes with polymerase fidelity. The status of base excision repair may provide a biomarker for the sensitivity of individuals to manganese.
authors.affiliation: Florida A&M University, College of Pharmacy & Pharmaceutical Sciences, 1520 Martin Luther King Boulevard, Dyson Building Room 221, Tallahassee, FL 32307, USA.
authors.forename: Adrienne P
authors.initials: AP
authors.lastname: Stephenson
authors.forename: Tryphon K
authors.initials: TK
authors.lastname: Mazu
authors.forename: Jana S
authors.initials: JS
authors.lastname: Miles
authors.forename: Miles D
authors.initials: MD
authors.lastname: Freeman
authors.forename: R Renee
authors.initials: RR
authors.lastname: Reams
authors.forename: Hernan
authors.initials: H
authors.lastname: Flores-Rozas
mesh_terms: D000483:Alleles; D000975:Antioxidants / Q000494:pharmacology; D004260:DNA Repair / Q000187:drug effects*; D008274:Magnesium / Q000494:pharmacology; D008345:Manganese / Q000633:toxicity*; D009154:Mutation / Q000235:genetics; D059645:Mutation Rate; D010641:Phenotype; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000187:drug effects / Q000235:genetics*
chemical_list: D000975:Antioxidants; D008345:Manganese; D008274:Magnesium