Nickel induces a signature mutation for oxygen free radical damage

We have determined the specificity of mutations produced by nickel(II), a known human carcinogen, in a forward mutation assay and also used a sensitive reversion assay to show that Ni(II), like iron and copper, can produce tandem double CC-->TT mutations, a hallmark of damage to DNA by either UV irradiation or oxygen free radicals. A reduction in mutation frequencies by the addition of oxygen radical scavengers also supports the involvement of reactive oxygen species in DNA damage and mutagenesis by Ni(II). Mutagenesis by Ni(II) is enhanced by the addition of both hydrogen peroxide and a tripeptide glycyl-glycyl-L-histidine. The enhancement of mutagenesis of Ni(II) by the tripeptide indicates that these complexes could serve to localize Ni(II) in nuclei and mediate DNA damage and mutagenesis via the generation of short-lived oxygen free radicals. These data suggest that Ni(II) carcinogenesis may proceed via the generation of active oxygen species and furthermore provide a model for nickel carcinogenesis based on the binding of Ni(II) to nuclear proteins.