Unmasking a killer: DNA O-6-methylguanine and the cytotoxicity of methylating agents

Methylating agents are potent carcinogens that are mutagenic and cytotoxic towards bacteria and mammalian cells. Their effects can be ascribed to an a bility to modify DNA covalently, Pioneering studies of the chemical reactiv ity of methylating agents towards DNA components and their effectiveness as animal carcinogens identified O-6-methylguanine (O(6)meG) as a potentially important DNA lesion. Subsequent analysis of the effects of methylating ca rcinogens in bacteria and cultured mammalian cells - including the discover y of the inducible adaptive response to alkylating agents in Escherichia co li have defined the contributions of O(6)meG and other methylated DNA bases to the biological effects of these chemicals. More recently, the role of O (6)meG in killing mammalian cells has been revealed by the lethal interacti on between persistent DNA O(6)meG and the mismatch repair pathway. Here, we briefly review the results which led to the identification of the biologic al consequences of persistent DNA O(6)meG. We consider the possible consequ ences for a human cell of chronic exposure to low levels of a methylating a gent. Such exposure may increase the probability that the cell's mismatch r epair pathway becomes inactive. Loss of mismatch repair predisposes the cel l to mutation induction, not only through uncorrected replication errors bu t also by methylating agents and other mutagens. (C) 2000 Elsevier Science B.V. All rights reserved.