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

Details

• Alternative Title:
  Biomed Res Int
• Personal Author:
  Stephenson, Adrienne P. ; Mazu, Tryphon K. ; Miles, Jana S. ; Freeman, Miles D. ; Reams, R. Renee ; Flores-Rozas, Hernan
• Description:
  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.
• Subjects:
  Alleles Antioxidants DNA Repair Magnesium Manganese Mutation Mutation Rate Phenotype Saccharomyces Cerevisiae
• Source:
  Biomed Res Int. 2013; 2013.
• Pubmed ID:
  24282812
• Pubmed Central ID:
  PMC3825218
• Document Type:
  Journal Article
• Funding:
  2 G12 RR003020/RR/NCRR NIH HHS/United States ; 3U50TS473408-05W1/TS/ATSDR CDC HHS/United States ; 5S11ES01187-05/ES/NIEHS NIH HHS/United States ; 8 G12 MD007582-28/MD/NIMHD NIH HHS/United States ; G12 MD007582/MD/NIMHD NIH HHS/United States
• Volume:
  2013
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:6065748260c0987fea42910abc27eb1a848608950bacaa3cd7c96848d8544df5
• Download URL:
  https://stacks.cdc.gov/view/cdc/22548/cdc_22548_DS1.pdf
• File Type:
  [PDF - 1.04 MB ]