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

Abstract EN

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.