MECHANISMS OF MUTAGENESIS BY CHEMICAL CARCINOGENS

一个突变就能把正常基因变成致癌基因 衍生物证明了诱变的潜在重要性 癌症的病因学过程。 因此，理解A 致癌物诱导的突变可能阐明其 致癌性 这个项目的目标是确定如何 化学致癌物导致突变，使用细菌作为模型， 系统 研究的重点是突变的机制， 一些具有环境或医学意义的遗传毒性物质 导致典型的DNA损伤 遗传和 生物化学方法用于确定DNA损伤是什么 他们是如何被诱导的，他们如何被修复，这会引起突变， 什么样的细胞功能参与诱变过程，以及 突变的结果是什么 具体目标是： 1. 为探讨黄曲霉毒素B1的致突变机理， 这会对DNA造成巨大损伤 缺陷的影响 细菌功能影响准确性和致突变性 将表征黄曲霉毒素诱导的DNA损伤的修复。 的 体外产生的确定的DNA损伤的致突变潜力 将确定直接作用的黄曲霉毒素类似物。 2. 确定卤代物引起的主要致突变性损伤 芳香烃. 错误编码的病变被证明是由 1，2-二溴乙烷将通过生物化学方法进行鉴别。 途径 这些损伤修复和它们由其他 卤代烃将被检测 3. 研究DNA的致突变性和毒性潜力 由化学治疗剂，顺- 二氯二氨铂 修复的贡献 该试剂的毒性和致突变性的中间体将 被确定。

That a single mutation can change a normal gene into its oncogenic derivative demonstrates the potential importance of mutagenic processes in the etiology of cancer. Thus, understanding how a carcinogen induces mutations may elucidate the basis of its carcinogenicity. The goal of this project is to determine how chemical carcinogens cause mutations, using bacteria as a model system. The research focuses on the mechanisms of mutagenesis of a few environmentally or medically significant genotoxic agents that cause representative classes of DNA damage. Genetic and biochemical methods are used to determine what DNA lesions are induced, how they may be repaired, which give rise to mutations, what cellular functions participate in the mutagenic process, and what mutations result. The specific aims are: 1. To investigate the mechanism of mutagenesis of aflatoxin Bl, which makes bulky lesions to DNA. The effects of defects in bacterial functions affecting both the accurate and mutagenic repair of aflatoxin-induced DNA lesions will be characterized. The mutagenic potential of defined DNA lesions generated in vitro by a direct-acting aflatoxin analog will be determined. 2. To identify the major mutagenic lesions induced by halogenated hydrocarbons. The miscoding lesions demonstrated to be induced by 1,2-dibromoethane will be identified biochemically. Pathways for the repair of these lesions and their induction by other halogenated hydrocarbons will be examined 3. To investigate the mutagenic and toxic potential of the DNA lesions ' induced by the chemotherapeutic agent, cis- diamminedichloroplatinum II. The contribution of repair intermediates to the toxicity and mutagenicity of this agent will be determined.