On the quantitative relationship between O6-methylguanine residues in genomic DNA and production of sister-chromatid exchanges, mutations and lethal events in a Mer- human tumor cell line.

Abstract O 6 -Methylguanine (m6G) is an altered base produced in DNA by S N 1 methylating agents such as N -methyl- N ′-nitro- N -nitrosoguanidine (MNNG). This lesion is repaired by the protein O 6 -methyl-guanine- DNA methyltransferase (MGMT) in normal human cell lines, but is not repaired in certain human tumor lines that are termed Mex − or Mer − . Compared with repair-proficient cell lines, such repair-deficient tumor lines are hypersensitive to the production by MNNG of sister-chromatid exchanges (SCE), mutations and lethality. We report here that MNNG treatment produces 1 SCE for every 42 ± 10 m6G formed in the genome of Mer − tumor cells, 1 6TG-resistant mutant for every 8 (range of 5–14) m6G produced statistically in the coding region of the hypoxanthine phosphoribosyltransferase gene, and 1 lethal event per 6650 ± 1200 m6G. In addition, in vitro base mismatch incision at m6G : BrU pairs was similar to that at m6G : T pairs, the lesions that likely initiate SCE production. We conclude that m6G residues in genomic DNA are very recombinogenic as well as highly mutagenic in Mer − human tumor cells. The results are interpreted in terms of the relationship between methylation-induced SCE and G : T mismatch recognition.