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

Bignami, M, O'Driscoll, M, Aquilina, G and Karran, P (2000) Unmasking a killer: DNA O(6)-methylguanine and the cytotoxicity of methylating agents. Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, 462 (2-3). pp. 71-82. ISSN 0027-5107

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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 O(6)-methylguanine (O(6)meG) 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 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 interaction between persistent DNA O(6)meG and the mismatch repair pathway. Here, we briefly review the results which led to the identification of the biological consequences of persistent DNA O(6)meG. 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.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Subjects: Q Science > QM Human anatomy > QM0001 General
R Medicine > RB Pathology
Depositing User: Mark O'Driscoll
Date Deposited: 22 Nov 2013 12:02
Last Modified: 22 Nov 2013 12:02
URI: http://srodev.sussex.ac.uk/id/eprint/46971
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