Fast repair of O 6 -ethylguanine, but not O 6 -methylguanine, in transcribed genes prevents mutation of H- ras in rat mammary tumorigenesis induced by ethylnitrosourea in place of methylnitrosourea

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Abstract
Differential repair of structurally distinct mutagenic lesions in critical genes may influence the cellular risk of malignant conversion. We have investigated rat mammary tumorigenesis induced by N-ethyl-N-nitrosourea (EtNU) versus N-methyl-N-nitrosourea (MeNU) with respect to tumor incidence, ras gene mutation, and gene-specific repair. Both carcinogens induced mammary adenocarcinomas at high yield. In mammary epithelia (very low expression of O6-alkylguanine-DNA alkyltransferase, MGMT), O6-methylguanine (O6-MeGua) was eliminated from transcribed (H-ras and β-actin) and inactive genes (IgE heavy chain) at the same slow rate as determined for bulk genomic DNA. The persistence of O6-MeGua in DNA correlated with a high frequency of G:C → A:T transition mutations at codon 12 of the H-ras gene in MeNU-induced tumors. Repair of O6-ethylguanine (O6-EtGua), too, was slow in the IgE heavy chain gene as in bulk DNA. Contrasting with O6-MeGua, however, O6-EtGua was removed ≈20 times faster from the active H-ras and β-actin genes via MGMT-independent mechanism(s). Accordingly, no H-ras codon 12 mutations were found in EtNU-induced tumors, and 5- to 8-fold surplus alkyltransferase activity of the mammary epithelia—via a bacterial ada transgene—did not significantly counteract tumorigenesis in EtNU-exposed contrary to MeNU-treated animals. Neither MeNU- nor EtNU-induced tumors exhibited mutations at codons 13 and 61 of H-ras or codons 12, 13, and 61 of K-ras. Fast repair of O6-EtGua, but not O6-MeGua, in transcribed genes thus prevents mutational activation of H-ras when rat mammary carcinogenesis is initiated by EtNU in place of MeNU.

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