| Mutagenesis by Metal-induced Oxygen Radicals Environ Health Perspect Key words: mutagenesis, metals, oxygen radicals, mutation spectra, DNA polymerases
This paper was presented at the Second International Meeting on Molecular Mechanisms of Metal Toxiciity and Carcinogeniciity held 10-17 January 1993 in Madonna di Campiglio, Italy.
These studies were supported by National Institutes of Health grants CA08855 to T.M.R., and CA39903 and AG01751 to L.A.L.
Address correspondence to Dr. Lawrence A. Loeb, Joseph Gottstein Memorial Cancer Research Laboratory, Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, Telephone 206-543-6015. Fax 206-543-3967.
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To assess the contribution of reactive oxygen species (ROS) to metal-induced mutagenesis, we have determined the spectrum of mutations in the lacZalpha gene after exposure of M13mp2 DNA to Fe2+, Cu2+, and Ni2+. With iron and copper ions, mutations are clustered and are predominantly single-base substitutions. Fe, Cu, and phorbol ester-stimulated neutrophils also produced tandem double CC->TT mutations. This mutation may provide a marker for the role of oxidative damage in carcinogenesis. Mutagenesis by Ni2+ required the complexing of the metal to a tripeptide and the addition of H2O2. To assess the contribution of ROS in mammalian cells, we determined the spectrum of mutations produced when purified DNA polymerases-alpha and -beta synthesized DNA using a template that had been damaged by ROS. The mutation spectra produced by the two polymerases indicates that these enzymes substitute different nucleotides opposite the same lesions. -- Environ Health Perspect 102(Suppl 3) :57-61 (1994) . Key words: mutagenesis, metals, oxygen radicals, mutation spectra, DNA polymerases
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