Biologically Significant Damage in DNA

描述（由申请人提供）：电离辐射在生命系统中引起突变、转化和致死效应。DMA损伤与这些效应密切相关。这项工作的长期目标是阐明电离辐射在细胞环境中产生DNA损伤的辐射化学机制，以及通过这些机制可以修改和修复DNA损伤。这将允许评估细胞系统科普这种损伤的能力，并且还提供了设计影响这些过程的改进方法的手段，例如使用放射增敏剂和放射防护剂。DNA损伤产物的性质和空间分布受到电离机制、电离事件的聚集、以及附近化学物质的存在，例如DNA结合蛋白中的氨基酸残基。这些过程的这些影响是孤立而不是结合起来理解的。我们的方法使用可适应的模型系统，我们可以单独调整流程。我们使用寡聚赖氨酸、乳糖阻遏蛋白和组蛋白来研究DNA结合蛋白的作用。DNA损伤通常作为质粒靶中的链断裂或碱基损伤来检测，也作为特定的低分子量产物5-亚甲基呋喃酮和8-氧代-7，8-二氢鸟嘌呤来检测，其可以通过色谱法鉴定。由于DNA损伤是在受控条件下产生的，因此我们可以用速率常数和中间产物的寿命来定量描述这一过程。其结果将是更好地了解DNA损伤是如何在生理条件下产生的。随着对核能的重新重视，关于长期储存放射性废物的辩论以及与恐怖主义有关的问题，人们对电离辐射的危害表示严重关切。合理的风险评估需要了解所涉及的机制。对人类健康的应用包括确定辐射敏感性个体差异的原因，以及开发低剂量和低剂量率照射的癌症病因风险估计的机械模型。

DESCRIPTION (provided by applicant): Ionizing radiation causes mutation, transformation, and lethal effects in living systems. DMA damage is intimately involved in these effects. The long term goals of this work are to clarify the radiation chemical mechanisms by which DNA damage is produced by ionizing radiation in the cellular environment, and by which it may be modified and repaired. This will permit an evaluation of the ability of cellular systems to cope with this damage, and also provide the means to design improved methods of influencing these processes, for example with radiosensitizers and radioprotectors The nature and spatial distribution of the DNA damage products is strongly influenced by the ionization mechanism, the clustering of the ionization events, and also by the presence of nearby chemical species such as amino acid residues in DNA binding proteins. These effects of these processes are understood in isolation but not in combination. Our approach uses adaptable model systems with which we can adjust the processes individually. We use oligo-arginines, the lac represser, and histones to examine the effects of DNA binding proteins. The DNA damage is detected as in general as strand breaks or base damages in plasmid targets, and also as the particular low molecular weight products 5-methylenefuanone and 8-oxo-7,8-dihydroguanine which can be identified chromatographically. Because the DNA damage is produced under controlled conditions, we can make a quantitative description of the processes in terms of rate constants and lifetimes of intermediates. The result will be an improved understanding of how DNA damage is produced under physiological conditions. With a renewed emphasis on nuclear power, debate over long term storage of radioactive waste, and terrorism related issues, there is a substantial concern about the hazards associated with ionizing radiation. Rational risk estimation requires an understanding of the mechanisms involved. Applications to human health include defining the causes of individual variation in radiosensitivity and the development of mechanistic models for risk estimation of cancer etiology by low dose and low dose rate exposures.