SPONTANEOUS AND GENOTOXICANT INDUCED MUTATION MECHANISMS

这项研究的目的是了解其分子机制。 自发和遗传毒物诱导的重复DNA突变 可以采用替代二级结构的序列。申请人 继续检验某些DNA序列形成次级DNA序列的假设 DNA定向自发诱变的结构底物 突变事件(DNA定向突变)。与这些DNA相关的突变 序列会导致癌症和人类疾病。第一个目标是理解 导致三联体重复不稳定的分子机制与 13种神经退行性疾病，包括1型强直性肌营养不良， 脆性X综合征和Friedreich共济失调，使用敏感的基因分析 在大肠杆菌中重复不稳定。第二个目标涉及理解 重复突变的分子机制和领先/滞后的特异性。 第三个目标是寻求了解突变热点的基础 分子间链切换事件将准回文纠正为完美 反向重复。第四个目标将决定DNA复制的作用， 自发DNA二级结构突变中的修复和重组。 第五个目标将检验以下假设：某些化学物质和环境 诱变剂可提高DNA二级结构的诱变率。辛登博士 将检查多种化学和环境遗传毒物的影响， 包括紫外线照射、X射线照射、丝裂霉素C、乙基亚硝脲(ENU)和 乙基甲烷磺酸盐(EMS)、顺铂、N-甲基-N‘-硝基N-亚硝基 (MNNG)、多环芳烃和N-亚硝胺，包括 烟碱(4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone)和N‘-亚硝基烟碱 (NNN)。这些实验将提供对分子的理解。 自发性和遗传毒物诱导的机制和途径 诱变。

The goal of this research is to understand the molecular mechanisms of spontaneous and genotoxicant induced mutagenesis of repeated DNA sequences that can adopt alternative secondary structures. The applicant continues to test the hypothesis that certain DNA sequences form secondary structure substrates for spontaneous mutagenesis resulting in DNA-directed mutation events (DNA-directed mutations). Mutations associated with these DNA sequences cause cancer and human disease. The first aim is to understand the molecular mechanisms responsible for triplet repeat instability associated with thirteen neurodegenerative diseases, including myotonicdystrophy type 1, Fragile X syndrome, and Friedreich's Ataxia, using sensitive genetic assays for repeat instability in Escherichia coli. A second aim involves understanding the molecular mechanisms and leading/lagging specificity of duplication mutations. A third aim seeks to understand the basis for a mutation hotspot for intermolecular strand switch events that correct quasipalindromes to perfect inverted repeats. The fourth aim will determine the role of DNA replication, repair and recombination in spontaneous DNA secondary structure mutagenesis. The fifth aim will test the hypothesis that certain chemical and environmental mutagens increase the rate of DNA secondary structure mutagenesis. Dr. Sinden will examine the effect of numerous chemical and environmental genotoxicants, including UV irradiation, X-radiation, mitomycin C, ethylnitrosourea (ENU) and ethylmethane sulfonate (EMS), cisplatin, N-methyl-N'-nitro N-nitrosoguanidine (MNNG), polycyclic aromatic hydrocarbons, and N-nitrosamines including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN). These experiments will provide an understanding of the molecular mechanisms and pathways involved in spontaneous and genotoxicant-induced mutagenesis.