MUTAGENESIS AND ITS CONTROL IN E. COLI

拟议研究的长期目标是从分子水平了解 生物体的突变率是如何定义的， 速率响应于环境诱变剂而增加。 的 菌E.选择大肠杆菌来研究这些问题是因为 它提供了一个相对简单的实验系统， 遗传和生物化学方法。 赠款的具体目的是 学习： (1)确定DNA复制保真度的酶机制; (2)DNA损伤诱导SOS反应的调节和范围， 包括增加突变率和增强DNA修复能力。 复制保真度的工作最初将集中在生物化学分析上 聚合酶III全酶的α和ε亚基， 似乎是正常的准确性的主要决定因素 在E.杆菌 3'的贡献和可能的调节 产量5'核酸外切酶（编辑功能）将是特别关注的。 研究 SOS响应的定义将寻求：（i）DNA的分子信号 （二）引发SOS反应的生物化学基础; （三）对案件的处理;（四）对案件的处理; 其他类型的遗传变异的术语，如转座和 重复。 对突变率及其控制的理解是可能的 与理解癌症的起始事件有关。 许多 在动物中致癌的物质激活SOS反应， 细菌 癌症通常可能源于一种细胞因子的异常激活。 体细胞中的SOS样系统，其正常目的是诱导 生殖细胞的遗传变异。

The long term goal of the proposed research is a molecular understanding of how the mutation rate of an organism is defined and how this basal mutation rate is increased in response to environmental mutagenic agents. The bacterium E. coli has been chosen for the study of these questions because it provides a relatively simple experimental system amenable to combined genetic and biochemical approaches. Specific aims of the grant are to learn: (1) enzymatic mechanisms that define the fidelity of DNA replication; (2) regulation and scope of the induced SOS response to DNA damage, which includes increased mutation rate and enhanced capacity for DNA repair. Work on replication fidelity will focus initially on a biochemical analysis of the Alpha and Epsilon subunits of polymerase III holoenzyme, which appear to be the primary determinants for the accuracy of normal replication in E. coli. The contribution and possible regulation of the 3' Yield 5' exonuclease (editing function) will be of special concern. Study of the SOS response will seek to define: (i) the molecular signal of DNA damage that initiates the SOS response; (ii) the biochemical basis for the increase in replication errors; (iii) the scope of the SOS response in terms of other types of genetic variation, such as transposition and duplication. An understanding of mutation rate and its control is likely to be pertinent for an understanding of initiating events in cancer. Many agents that are carcinogenic in animals activate the SOS response in bacteria. Cancer might often derive from the aberrant activation of an SOS-like system in somatic cells, the normal purpose of which is inducible genetic variation in germ cells.