A role for Pms2 in the prevention of tandem CC --> TT substitutions induced by ultraviolet radiation and oxidative stress.
DNA mismatch repair (MMR) is important for preventing base-pair substitutions caused by spontaneous or damage-related DNA polymerase errors. We have used a reversion assay based on mouse Aprt to investigate the role of MMR in preventing ultraviolet radiation (UV) and oxidative stress induced tandem CC --> TT base pair substitutions in cultured mammalian cells. The reversion construct used for this assay can detect both C --> T and CC --> TT mutational events. Most spontaneous mutations in Pms2-deficient cells were single C --> T substitutions (88%), with the remainder being tandem CC --> TT substitutions (12%). The percentage of tandem CC --> TT substitutions rose to 64% and 94% for Pms2-deficient cells exposed to UV and a mixture of hydrogen peroxide and metals (Cu/Fe), respectively. Exposure to hydrogen peroxide alone or metals alone did not induce the tandem substitutions, nor did treatment of the cells with the alkylating agent ethylmethane sulfonate, which induces G --> A substitutions on the opposite strand. Tandem CC --> TT substitutions were also induced by UV irradiation and the hydrogen peroxide/metal mixture in Pms2-proficient cells, but at frequencies significantly lower than those observed in the Pms2-deficient cells. We conclude that mismatch repair plays an important role in preventing tandem CC --> TT substitutions induced by certain genotoxin exposures.
Shin-Darlak
Chi Y
CY
Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, Portland, OR 97239, USA.
Skinner
Amy M
AM
Turker
Mitchell S
MS
D000228:Adenine Phosphoribosyltransferase / Q000235:genetics*; D000251:Adenosine Triphosphatases / Q000235:genetics*; D000818:Animals; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D006861:Hydrogen Peroxide / Q000633:toxicity; D008670:Metals / Q000633:toxicity; D051379:Mice; D000070976:Mismatch Repair Endonuclease PMS2; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics; D017422:Sequence Analysis, DNA; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
D004268:DNA-Binding Proteins; D008670:Metals; D006861:Hydrogen Peroxide; D000228:Adenine Phosphoribosyltransferase; D000251:Adenosine Triphosphatases; C499533:Pms2 protein, mouse; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes