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Carcinogenesis, Vol. 21, No. 7, 1397-1402, July 2000
© 2000 Oxford University Press

Carcinogenesis

Enhanced in vivo repair of O4-methylthymine by a mutant human DNA alkyltransferase

Lance P. Encell and Lawrence A. Loeb1

The Joseph Gottstein Memorial Cancer Research Laboratory, Departments of Pathology and Biochemistry, University of Washington School of Medicine, Seattle, WA 98195-7705 USA

The repair of O6-methylguanine (m6G) by human O6-alkylguanine-DNA alkyltransferase (hAGT) is ~5000-fold greater than that for O4-methylthymine (m4T). To evaluate each adduct's contribution to mutagenesis, we previously created a mutant hAGT with increased specificity for m4T in vitro. The mutant and wild-type (WT) hAGT have now been expressed in bacterial strains that allow for the specific detection of A:T->G:C and G:C->A:T mutations induced by m4T and m6G, respectively. After exposure to the mutagenic methylating agent, N-methyl-N'-nitro-N-nitrosoguanidine, A:T->G:C substitutions were reduced >4-fold in cells expressing the mutant hAGT compared with 1.1-fold for WT hAGT. G:C->A:T substitutions were decreased >2.5-fold in cells expressing the mutant hAGT, whereas WT hAGT totally prevented G:C->A:T mutations. These results demonstrate that the altered substrate specificity of hAGT observed in vitro also occurs in vivo, and that it is responsible for the observed differences in mutations.


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