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Role of Depurination in Mutagenesis by Chemical Carcinogens¹

The Joseph Gottstein Memorial Cancer Research Laboratory, Department of Pathology, School of Medicine, University of Washington, Seattle, Washington 98195 [R. M. S., L. A. L.], and Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 [B. W. G.]

The effect of modifying 174 viral DNA by the chemical carcinogens ß-propiolactone, N-acetoxyacetylaminofluorene and anti-benzo[a]pyrene diol-epoxide was investigated by transfecting the modified DNA into Escherichia coli spheroplasts. Modification of the DNA in vitro by each of these agents was mutagenic for the 174 amber mutants am3 and am86. Mutagenicity depended on the induction of the "SOS" response in the host spheroplasts. Heating ß-propiolactone-treated DNA at neutral pH caused strong inactivation such that the number of lethal hits was increased 4-fold. Sucrose gradient analysis showed the induction of alkali-labile sites in the heated DNA. The "nicked circle assay" with double-stranded 174 DNA showed greater than 70% of these sites to be apurinic sites. Concomitantly with the production of these new sites, a strong increase in the mutation frequency was observed. This mutagenesis also depended upon the induction of the error-prone SOS response in the spheroplasts, as was previously shown to be the case for mutagenesis at putative apurinic sites induced directly by acid-heat treatment. These results suggest that depurination may be of importance to the mechanism of mutagenesis by ß-propiolactone and other carcinogens.

¹ This investigation was supported by grants from NIH (CA-24845, Ca-24998, and AG-01751) and the National Science Foundation (PCM-76-80439).

² Present address: Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, N. C. 27709.

³ To whom requests for reprints should be addressed.

Received 12/31/81. Accepted 5/28/82.

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