SPONTANEOUS AND GENOTOXICANT INDUCED MUTATION MECHANISMS

自发和基因毒性诱导的突变机制

• 批准号: 6518060
• 负责人: RICHARD Rankin SINDEN
• 金额: $ 31.83万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-12-14 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6518060
• 关键词: DNA damage; DNA repair; DNA replication; Escherichia coli; bacterial genetics; environmental toxicology; gene mutation; genetic recombination; molecular genetics; mutagen testing; mutagens; nucleic acid sequence

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.

这项研究的目的是了解分子机制 自发和遗传毒物诱导的重复 DNA 诱变 可以采用替代二级结构的序列。申请人 继续检验某些 DNA 序列形成次级序列的假设 自发诱变的结构底物，导致 DNA 定向 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。第一个目标是了解 导致三联体重复不稳定性的分子机制 13 种神经退行性疾病，包括 1 型强直性肌营养不良， 脆性 X 综合征和弗里德赖希共济失调，使用敏感的基因检测 大肠杆菌中重复不稳定。第二个目标涉及了解 重复突变的分子机制和领先/滞后特异性。 第三个目标旨在了解突变热点的基础 分子间链转换事件将准配体纠正为完美 反向重复。第四个目标将确定 DNA 复制的作用， DNA 二级结构自发突变中的修复和重组。 第五个目标将检验以下假设：某些化学和环境 诱变剂增加 DNA 二级结构诱变的速率。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、丝裂霉素 C、乙基亚硝基脲 (ENU) 和 甲磺酸乙酯 (EMS)、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-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮 (NNK) 和 N'-亚硝基降烟碱 （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。