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© 1985 Oxford University Press

research-article

Extent of formation of O4-methylthymidine in calf thymus DNA methylated by N-methyl-N-nitrosourea and lack of repair of this product by rat liver O6-alkylguanine-DNA-alkyltransferase

M.Eileen Dolan and Anthony E. Pegg 1

Department of Physiology and Cancer Research Center, The Milton S.Hershey Medical Center, The Pennsylvania State University College of Medicine P.O. Box 850, Hershey, PA 17033, USA

1To whom reprint requests should be sent

Calf thymus DNA was methylated by reaction with N-[3H]-methyl-N-nitrosourea and the content of O6-methyldeoxy-guanosine, 3-methylthymidine and O4-methylthymidine was determined. It was found that O4-methylthymidine represented only 0.06 ± 0.02% of the total methylation and that the ratio of O6-methyldeoxyguanosine: O4-methylthymidine was 126 ± 31. 3-Methylthymidine represented only 0.05 ± 0.01% of the total radioactivity and the ratio of O6-methyl-deoxyguanosine: 3-methylthymidine was 171 ± 16. The ability of O6-alkylguanine-DNA-alkyltransferases from Escherichia coli and from rat liver to repair O4-methylthymidine was determined using this methylated DNA as a substrate. When the methylated DNA substrate was incubated with an excess of either of the O6-alktylguanine-DNA-alkyltransferases > 95% of the O6-methyldeoxyguanosine was removed. The E. coli O6-alkylguanine-DNA-alkyltransferase also removed 89% of the O4-methylthymidine but the rat liver alkyltransferase did not alter the content of O4-methylthymidine. These results indicate that the mammalian O6-alkylguanine-DNA-alkyl-transferase is specific for O6-methylguanine and differs from the bacterial protein in that it does not demethylate O4-methylthymine at any significant rate. This shows that the rat O6- alkylguanine-DNA-alkyltransferase is not able to protect against the possible hazards of the promutagenic lesion, O4-methylthymidine, but the very low extent of formation of this product may limit its significance in carcinogenesis and mutagenesis.


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