MECHANISMS OF MUTAGENESIS BY ALFATOXIN AND OTHER AGENTS

大多数化学致癌物都是细菌诱变剂，这一事实强烈地 与致癌有关的DNA损伤。最近的研究发现，一个单一的 碱基改变是正常基因和正常基因之间唯一显著的区别 其致癌衍生物支持了一种假设，即一种特定的 突变可能至少是癌症病因学中的一个步骤。因此， 了解致癌物诱导突变的过程可能会导致 以了解其致癌性的基础。 本申请中提出的研究的总体目标是 阐明化学致癌物是如何导致细菌突变的。少校 焦点放在重要的人类致癌物质黄曲霉毒素的致突变性上 B1，它与DNA产生巨大的加合物。第二个焦点是 烷基化剂的致突变性，如 N-甲基-N‘-硝基-N-亚硝胺和甲烷磺酸甲酯，其 将简单的烷基转移到DNA碱基上。这两种类型的诱变剂 损伤与细菌功能的相似性质有关 它们的修复，通过这些可能产生的共同中间体 修复功能，以及它们的修复中间体是 很可能本身就是诱变的。遗传和生化方法将是 用来确定这些制剂诱发的预致突变损伤， 细菌修复它们的功能，损伤是如何转化为 突变，以及突变会导致什么。这项研究的具体目的 包括： 1.产生和表征影响细菌功能的缺陷 DNA损伤的准确修复和致突变修复 黄曲霉毒素B1。 2.确定已知修复功能中的缺陷对 烷基化试剂诱发突变的频率和特异性。 这些目标的实现将导致确定和 修复DNA损伤的细胞活动的特征 阐明这些活动如何相互作用以产生突变。 这些知识可能与理解后果直接相关 高等生物体的DNA损伤。

The fact that most chemical carcinogens are bacterial mutagens has strongly implicated DNA damage in carcinogenesis. The recent finding that a single base change is the only significant difference between a normal gene and its oncogenic derivative has supported the hypothesis that a specific mutation may be at least one step in the etiology of cancer. Thus understanding the process by which a carcinogen induces mutations may lead to the understanding of the basis of its carcinogenicity. The overall goal of the research proposed in this application is to elucidate how chemical carcinogens cause mutations in bacteria. The major focus is on the mutagenicity of the important human carcinogen aflatoxin B1, which makes bulky adducts to DNA. A second focus is on the mutagenicity of alkylating agents, such as N-methyl-N'-nitro-N-nitrosoguanidine and methyl methanesulfonate, which transfer simple alkyl groups to DNA bases. These two types of mutagenic damage are related by the similar nature of the bacterial functions for their repair, by the common intermediates that may be generated by these repair functions, and by the fact that their repair intermediates are likely to be themselves mutagenic. Genetic and biochemical methods will be used to determine the premutagenic lesions that these agents induce, the bacterial functions that repair them, how the lesions are converted to mutations, and what mutations result. The specific aims of this research are: 1. To generate and characterize defects in bacterial functions affecting both the accurate and mutagenic repair of the DNA lesions induced by aflatoxin B1. 2. To determine the effects of defects in known repair functions on the frequency and specificity of mutations induced by alkylating agents. The achievement of these aims will lead to the identification and characterization of the cellular activities that repair DNA damage and to the elucidation of how these activities may interact to produce mutations. Such knowledge may be directly relevant to understanding the consequences of DNA damage in higher organisms.