Metal replacement in DNA-binding zinc finger proteins and its relevance to mutagenicity and carcinogenicity through free radical generation.

Carcinogenesis induced by metals is well documented, but the mechanism of cancer induction is not clear. It is known that transition metals can damage DNA by free radicals generated by Fenton reaction. We are investigating a class of DNA-binding proteins, known as zinc finger proteins, which act as transcription factors binding specifically to short DNA-sequences and controlling the transcription of a number of genes. We have demonstrated the ability of metals such as cobalt, cadmium, copper, nickel, and iron to substitute for zinc in zinc finger protein. The results gave further insight on the structural contribution of metal toward DNA-binding and identified metal interactions that may be of relevance to metal-induced DNA damage and carcinogenesis. The key to the mechanism of metal-mediated carcinogenesis is the enhancement of cellular redox processing by metals. Cobalt and iron in the presence of H2O2 catalyze the degradation of deoxyribose and induce DNA damage. Thus, a redox metal substituted for zinc in the zinc finger protein is expected to generate free radicals to cause DNA damage. Consequently, such metals bound to a DNA-binding protein generating potentially harmful free radicals in close proximity to DNA may be of relevance to the toxicity and carcinogenicity of these metals.