SPONTANEOUS AND GENOTOXICANT INDUCED MUTATION MECHANISMS

这项研究的目的是了解分子机制 自发和遗传毒性诱导的重复DNA突变 可以采用替代二级结构的序列。申请人 继续测试假设，某些DNA序列形成二级 导致DNA定向自发诱变的结构化底物 DNA定向突变（DNA directed mutations）与这些DNA相关的突变 序列导致癌症和人类疾病。第一个目的是了解 三重重复不稳定性的分子机制 13种神经变性疾病，包括1型肌强直性营养不良， 脆性X染色体综合征和弗里德赖希共济失调，使用敏感的基因检测， 大肠杆菌中的重复不稳定性。第二个目标是了解 重复突变的分子机制和前导/滞后特异性。 第三个目标是试图了解突变热点的基础， 分子间链转换事件，其将准回文酶校正为完美 反向重复序列第四个目标将确定DNA复制的作用， 自发DNA二级结构突变中的修复和重组。 第五个目标将检验某些化学和环境因素 诱变剂增加DNA二级结构诱变的速率。辛登医生 将检查许多化学和环境遗传毒物的影响， 包括UV照射、X-照射、丝裂霉素C、乙基亚硝基脲（ENU）和 甲基磺酸乙酯、顺铂、N-甲基-N '-硝基-N-亚硝基胍 （MNNG）、多环芳烃和N-亚硝胺，包括 4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）和N '-亚硝基去甲烟碱 （NNN）。这些实验将提供一个分子的理解 参与自发性和遗传毒性诱导的 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.