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Carcinogenesis, Vol. 21, No. 9, 1639-1646, September 2000
© 2000 Oxford University Press

Cancer Biology

Mismatch repair is required for O6-methylguanine-induced homologous recombination in human fibroblasts

Hong Zhang2, Giancarlo Marra1, Josef Jiricny1, Veronica M. Maher3 and J.Justin McCormick

Carcinogenesis Laboratory, Department of Microbiology, Department of Biochemistry and the Genetics Program, Food Safety and Toxicology Building, Michigan State University, East Lansing, MI 48824-1302, USA and
1 Institute for Medical Radiobiology, CH-8029 Zurich, Switzerland

O6-methylguanine is responsible for homologous recombination induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) [H.Zhang et al. (1996) Carcinogenesis, 17, 2229]. To test the hypothesis that mismatch repair is causally involved in this process, we generated mismatch repair-deficient strains from a human fibroblast line containing a substrate for detecting intrachromosomal homologous recombination. The four strains selected for study exhibited greatly increased resistance to the cytotoxic effects of MNNG, which was not affected by depletion of O6-alkylguanine-DNA alkyltransferase, and greatly increased sensitivity to the mutagenic effect of MNNG, suggesting that the mutagenic base modifications induced in these four cell strains by MNNG persist in their genomic DNA. Tests showed that their extracts are deficient in the repair of G:T mismatches. The frequency of homologous recombination induced by MNNG in three of these strains was significantly (5–7-fold) lower than that induced in the parental cell strain. This was not the result of a generalized defect in recombination, because when (±)-7ß,8{alpha}-dihydroxy-9{alpha},10{alpha}-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene was used to induce recombination, all three lines responded with a normal or even a somewhat higher frequency than that observed in the parental strain. The lack of recombination displayed by the fourth strain was shown to result from the loss of part of the recombination substrate. The results strongly suggest that functional mismatch repair is required for MNNG-induced homologous recombination.


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