Unmasking a killer: DNA O6-methylguanine and the cytotoxicity of methylating agents |
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| Institution: | 1. Istituto Superiore di Sanitá, Viale Regina Elena, 00161 Rome, Italy;2. Imperial Cancer Research Fund, Clare Hall Laboratories, Blanch Lane, South Mimms, Herts EN6 3LD, UK;1. Cancer and Blood Disease Institute, Cincinnati Children׳s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio;2. Hemangioma and Vascular Malformation Center, Cincinnati Children׳s Hospital Medical Center, 3333 Burnett Ave, Cincinnati, Ohio, 45229;1. Center for Proteomics and Systems Biology of The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA;2. Department of Nanomedicine and Biomedical Engineering, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA;1. Department of Dermatology, Mayo Clinic, Rochester, MN, USA;2. Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA;3. Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA;4. Division of Pediatric Hematology-Oncology, Mayo Clinic, Rochester, MN, USA |
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| Abstract: | Methylating agents are potent carcinogens that are mutagenic and cytotoxic towards bacteria and mammalian cells. Their effects can be ascribed to an ability to modify DNA covalently. Pioneering studies of the chemical reactivity of methylating agents towards DNA components and their effectiveness as animal carcinogens identified O6-methylguanine (O6meG) as a potentially important DNA lesion. Subsequent analysis of the effects of methylating carcinogens in bacteria and cultured mammalian cells — including the discovery of the inducible adaptive response to alkylating agents in Escherichia coli — have defined the contributions of O6meG and other methylated DNA bases to the biological effects of these chemicals. More recently, the role of O6meG in killing mammalian cells has been revealed by the lethal interaction between persistent DNA O6meG and the mismatch repair pathway. Here, we briefly review the results which led to the identification of the biological consequences of persistent DNA O6meG. We consider the possible consequences for a human cell of chronic exposure to low levels of a methylating agent. Such exposure may increase the probability that the cell's mismatch repair pathway becomes inactive. Loss of mismatch repair predisposes the cell to mutation induction, not only through uncorrected replication errors but also by methylating agents and other mutagens. |
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