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 O6-alkylguanine (O6AlkG) were examined for their propensity to undergo alkylation-induced apoptosis. Robust O6AlkG 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. O6AlkG repair had no effect on apoptosis induced by tumor necrosis factor alpha or by gamma-irradiation. We conclude that alkylating agents induce apoptosis by virtue of their ability to modify DNA bases and, more specifically, that O6AlkG lesions can trigger such programmed cell death.