Unmasking a killer:: DNA O6-methylguanine and the cytotoxicity of methylating agents
Unmasking a killer:: DNA O6-methylguanine and the cytotoxicity of methylating agents
复制标题
DOI：
10.1016/s1383-5742(00)00016-8
复制
发表时间：
2000-04-01
影响因子：
5.3
通讯作者：
Karran, P
中科院分区：
文献类型：
--
作者：
Bignami, M;O'Driscoll, M;Karran, P
甲基化剂是对细菌和哺乳动物细胞具有致突变性和细胞毒性的强效致癌物。它们的作用可以归因于共价修饰DNA的能力，甲基化试剂对DNA组分的化学反应性及其作为动物致癌物的有效性的开创性研究确定O-6-甲基鸟嘌呤（O（6）meG）是潜在的重要DNA损伤。随后对细菌和培养的哺乳动物细胞中甲基化致癌物的影响进行了分析，包括发现大肠杆菌对烷化剂的诱导适应性反应，确定了O（6）meG和其他甲基化DNA碱基对这些化学物质生物效应的贡献。最近，O（6）meG在杀死哺乳动物细胞中的作用已被持久DNA O（6）meG和错配修复途径之间的致命相互作用所揭示。在这里，我们简要回顾了导致持续DNA O（6）meG的生物学后果的鉴定结果。我们考虑了人类细胞长期暴露于低水平甲基化剂的可能后果。这种暴露可能会增加细胞的错配修复途径变得无活性的可能性。错配修复的丧失使细胞易于突变诱导，不仅通过未纠正的复制错误，而且通过甲基化剂和其他诱变剂。(C)2000 Elsevier Science B. V.保留所有权利。
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. (C) 2000 Elsevier Science B.V. All rights reserved.