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，并通过这种机制来修饰和修复DNA损伤。这将允许对细胞系统应对这种损伤的能力进行评估，并提供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保护剂。DNA损伤产物的性质和空间分布受到电离机制、电离事件的聚类以及附近化学物质的存在（如DNA结合蛋白中的氨基酸残基）的强烈影响。这些过程的影响是孤立的，而不是综合的。我们的方法使用可适应的模型系统，我们可以单独调整过程。我们使用低聚精氨酸、lac抑制因子和组蛋白来检测DNA结合蛋白的作用。DNA损伤一般可以检测到质粒靶中的链断裂或碱基损伤，也可以检测到特定的低分子量产物5-亚甲基芴酮和8-氧-7,8-二氢鸟嘌呤，这些产物可以色谱鉴定。由于DNA损伤是在受控条件下产生的，因此我们可以根据中间产物的速率常数和寿命对这一过程进行定量描述。结果将是对生理条件下DNA损伤是如何产生的更好的理解。随着对核能的重新重视，对放射性废物长期储存的争论，以及与恐怖主义有关的问题，人们对电离辐射的危害非常关注。合理的风险评估需要理解所涉及的机制。在人类健康方面的应用包括确定放射敏感性个体差异的原因，以及开发通过低剂量和低剂量率照射对癌症病因进行风险估计的机制模型。

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.