ON THE QUANTITATIVE RELATIONSHIP BETWEEN O-6-METHYLGUANINE RESIDUES IN GENOMIC DNA AND PRODUCTION OF SISTER-CHROMATID EXCHANGES, MUTATIONS AND LETHAL EVENTS IN A MER- HUMAN TUMOR-CELL LINE

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-methylguanine-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.