Mice defective in the DNA mismatch gene PMS2 are hypersensitive to MNU induced thymic lymphoma and are partially protected by transgenic expression of human MGMT

DNA mismatch repair (MMR) stabilizes the cellular genome, Mice defective in the MMR gene PMS2 are susceptible to spontaneous thymic lymphoma and sarco mas, To determine the sensitivity of PMS2 knockout mice to environmental ca rcinogens and the protective effect of O-6-methylguanine DIVA methyltransfe rase (MGMT), heterozygous PMS2 knockout mice and human MGMT (hMGMT) transge nic mice were mated and the PMS2(-/-) and PMS2(+/+) wit or without hMGMT of fspring were treated at 5 weeks of age with 50 mg/kg N-methgl-N-nitrosourea (MNU), MNU produces carcinogenic O-6-methylguanine (O-6-meG) adducts, resu lting in thymic lymphoma in mice, which can be prevented in normal mice by overexpression of hMGMT. A significantly higher incidence of thymic lymphom as,vas observed in MNU-treated PMS2(-/-) mice, compared to wildtype PMS2(+/ +) mice (100 ra 52%; P < 0.001), The mean latency of lymphomas was also sig nificantly shortened in PMS2(-/-) mice (81 vs 102 days, P<0.01), Transgenic expression of hMGMT significantly but incompletely blocked MNU lymphomagen esis in PMS2(-/-) mice. The incidence of lymphomas in PMS2(-/-)/hMGMT(+) mi ce was reduced to 80% (P<0.01) and mean latency increased to 91 days (P<0.0 5), Thy mic lymphomagenesis was efficiently blocked in PMS2(+/+)/hMGMT(+) m ice with rapid repair of O-6-meG, Since O-6-meG:T mismatches in MMR+ cells may trigger mismatch repair resulting in abortive repair and cell death whe reas in the absence of MMR, these mismatches are converted to A:T,,ve predi cted that G to A point mutations in codon 12 of the K-ras gene would occur. In this study, we found G to A point mutations in codon 12 of the K-ras ge ne in many tumors. Thus, in MMR deficient tissues, methylating agents induc e point mutations in cells with a higher rate of cell survival which togeth er are potently carcinogenic in the thymus, These data suggest that PMS2 de fective lymphomas may arise by the concerted action of environmental and pe rhaps endogenous methylation of DNA coupled to genomic instability.