O6-alkylguanine DNA lesions trigger apoptosis

It is unclear whether alkylating agents induce apoptosis because they damage DNA, or because they damage other cellular targets. Isogenic Chinese hamster ovary (CHO) cell lines varying in the repair of O-6-alkylguanine (O(6)AlkG) were examined for their propensity to undergo alkylation-induced apoptosis. Robust O(6)AlkG repair virtually eliminated the apoptogenic effects of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU, carmustine), as did the expression of BCL-2. O(6)AlkG repair had no effect on apoptosis induced by tumor necrosis factor or or by gamma-irradiation. We conclude that alkylating agents induce apoptosis by virtue of their ability to modify DNA bases and, more specifically, that O(6)AlkG lesions can trigger such programmed cell death.