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Mutagenesis by metal-induced oxygen radicals
1Joseph Gottstein Memorial Cancer Research Laboratory, Department of Pathology, University of Washington School of Medicine, Seattle 98195.
Environmental Health Perspectives
|September 1, 1994
Summary
Reactive oxygen species (ROS) contribute to metal-induced DNA mutations, particularly tandem double CC to TT changes, which may indicate oxidative damage in cancer. Different DNA polymerases introduce distinct mutations opposite ROS-damaged DNA templates.
Area of Science:
- Environmental Mutagenesis
- Molecular Toxicology
- Biochemistry
Background:
- Reactive oxygen species (ROS) are implicated in DNA damage and mutagenesis.
- Certain metal ions (Fe2+, Cu2+, Ni2+) can induce mutations.
- Oxidative stress is linked to carcinogenesis.
Purpose of the Study:
- To investigate the role of ROS in metal-induced mutagenesis.
- To characterize mutation spectra resulting from ROS exposure to DNA.
- To compare the mutagenic potential of different metal ions and ROS sources.
Main Methods:
- Exposure of M13mp2 DNA to Fe2+, Cu2+, and Ni2+ ions.
- Analysis of mutation spectra in the lacZ alpha gene.
- Assessment of DNA polymerase fidelity using ROS-damaged templates.
Main Results:
- Fe2+ and Cu2+ induced clustered single-base substitutions.
- Fe2+, Cu2+, and neutrophil-generated ROS produced tandem CC-->TT mutations.
- Ni2+ mutagenesis required complexation and hydrogen peroxide.
- DNA polymerases-alpha and -beta exhibited distinct nucleotide substitutions opposite ROS-induced DNA lesions.
Conclusions:
- ROS play a significant role in metal-induced mutagenesis.
- Tandem CC-->TT mutations may serve as a biomarker for oxidative damage in carcinogenesis.
- DNA polymerases exhibit differential fidelity in replicating ROS-damaged DNA, contributing to mutation spectrum diversity.