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Mechanism of mutagenesis by O6-methylguanine

Abstract

O6-methylguanine (O6meG) lesions of double-stranded DNA have been associated with mutation1–3 and neoplastic transformation4,5. These lesions can, in principle, be produced by at least three different mechanisms: direct alkylation of G·C base pairs in double-stranded DNA6,7; alkylation of guanine residues in single-stranded regions of DNA associated with replication forks8,9; and alkylation of the DNA precursor pool10 followed by incorporation of O6-methyl deoxyguanosine triphosphate (O6-medGTP) during DNA replication. DNA biosynthesis subsequent to all three events will generate predominantly O6-meG·T base pairs as O6meG preferentially pairs with T11,12. We show here that O6meG·T base pairs are mutagenic; that transalkylase repair1,13,14 has a direct role in the generation of mutations induced by alkylated pool nucleotides; and that the Escherichia coli mismatch repair system15,16 is capable of repairing mutagenic G·T intermediates.

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Eadie, J., Conrad, M., Toorchen, D. et al. Mechanism of mutagenesis by O6-methylguanine. Nature 308, 201–203 (1984). https://doi.org/10.1038/308201a0

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