Mutagenesis by metal-induced oxygen radicals.
To assess the contribution of reactive oxygen species (ROS) to metal-induced mutagenesis, we have determined the spectrum of mutations in the lacZ alpha 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.
Reid
T M
TM
Joseph Gottstein Memorial Cancer Research Laboratory, Department of Pathology, University of Washington School of Medicine, Seattle 98195.
Feig
D I
DI
Loeb
L A
LA
D001483:Base Sequence; D003300:Copper / Q000633:toxicity*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000633:toxicity*; D007938:Leukemia / Q000235:genetics; D008969:Molecular Sequence Data; D009153:Mutagens / Q000633:toxicity*; D009532:Nickel / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D009153:Mutagens; D017382:Reactive Oxygen Species; D003300:Copper; D009532:Nickel; D007501:Iron; D004259:DNA-Directed DNA Polymerase