Biologically Significant Damage in DNA

描述(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损害与这些影响密切相关。这项工作的长期目标是阐明辐射化学机制，通过这些机制，DNA损伤是由细胞环境中的电离辐射产生的，并且可以通过这些机制进行修改和修复。这将允许评估细胞系统处理这种损伤的能力，并提供设计改进的影响这些过程的方法的手段，例如使用辐射增敏剂和辐射保护剂。DNA损伤产物的性质和空间分布强烈地受到电离机制、电离事件的聚集以及附近化学物种的存在的影响，例如DNA结合蛋白中氨基酸残基的存在。这些过程的这些影响是单独理解的，而不是结合在一起理解的。我们的方法使用可适应的模型系统，通过该系统，我们可以单独调整流程。我们使用低聚精氨酸、乳胶抑制物和组蛋白来检测DNA结合蛋白的影响。DNA损伤一般表现为质粒靶标的链断裂或碱基损伤，也可以检测到特定的低分子产物5-亚甲基呋喃酮和8-氧代-7，8-二氢鸟嘌呤，它们可以通过层析进行鉴定。由于DNA损伤是在受控条件下发生的，因此我们可以用中间体的速率常数和寿命来定量描述这一过程。其结果将是更好地理解在生理条件下DNA损伤是如何产生的。随着对核能的重新重视，关于放射性废物长期储存的辩论，以及与恐怖主义有关的问题，人们对与电离辐射有关的危险有了很大的担忧。合理的风险评估需要了解所涉及的机制。在人类健康方面的应用包括确定辐射敏感性个体差异的原因，以及开发用于低剂量和低剂量率暴露的癌症病因风险评估的机制模型。

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.