Defects in Base Excision Repair Sensitize Cells to Manganese in S. cerevisiae

摘要

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. Mn²⁺ 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 Mn²⁺-mediated DNA damage using the yeast S. cerevisiae. The strains most sensitive to Mn²⁺ were those defective in base excision repair, glutathione synthesis, and superoxide dismutase mutants. Mn²⁺ 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 Mn²⁺ as well as its mutagenic effect was reduced by N-acetylcysteine, glutathione, and Mg²⁺. These data suggest that Mn²⁺ 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.