MECHANISMS OF FIDELITY AND MUTAGENESIS

这个项目的广泛的长期目标是了解突变是如何 发生于致癌物修饰的DNA的复制。 的目标 这项拨款申请是为了阐明DNA聚合酶 和DNA的小沟。 具体目标是确定 DNA小沟中的位点与DNA聚合酶相互作用 在复制过程中。 这些相互作用将在 正常DNA碱基的复制和致癌物质theta 6-甲基鸟嘌呤- 修改基础 观察到的正确和不正确之间的差异 复制将提供线索的机制，聚合酶用于 以高保真度复制DNA 该项目的健康相关性是 在致癌作用中。 正常DNA复制过程中发生的突变 致癌物质修饰的DNA会导致癌症。 了解 突变形成的机制可能使我们能够预测 化合物是诱变剂。 本研究设计合成DNA类似物 其中小沟中的位点被改变， 参与氢键。 结合改性的动力学 将测量相对于修饰的DNA的核苷酸三磷酸。 大 复制率的降低将表明改变的位点是 与聚合酶形成氢键。

The broad long-term goal of this project is to understand how mutations occur from the replication of carcinogen-modified DNA. The objective of this grant proposal is to elucidate the interactions between DNA polymerase and the minor groove of DNA. The specific aims are to determine which sites in the minor groove of the DNA interact with the DNA polymerase during replication. These interactions will be examined during the replication of the normal DNA bases and theta6-methylguanine, a carcinogen- modified base. Differences observed between correct and incorrect replication will give clues as to the mechanisms that polymerases use to replicate DNA with high fidelity. The health-relatedness of the project is in carcinogenesis. Mutations that occur during replication of normal DNA and carcinogen-modified DNA can lead to cancer. Understanding the mechanism of the formation of mutations might alloW us to predict which compounds are mutagens. The research design is to synthesize DNA analogs in which sites in the minor groove are altered so that they can not participate in hydrogen bonds. The kinetics of incorporation of modified nucleotide triphosphates opposite modified DNA will be measured. Large reduction in rates of replication will indicate that the altered site was involved in a hydrogen bond with the polymerase.