Biologically Significant Damage in DNA

描述（由申请人提供）：生物学的独特方面 与电离辐射相关的重要DNA损伤是这种损伤 是集群的。因此，它在性质上不同于紫外线产生的 辐射或化学品如烷基化剂。长期目标是 这项工作旨在阐明DNA损伤的辐射化学机制， 通过电离辐射引入，并通过其可以处理，修改，或 修复.这提供了一种评估蜂窝系统的能力的方法， 科普这种损害。对人类健康的应用包括确定原因 辐射敏感性的个体差异（例如， 抗氧化剂在防止辐射损伤）和发展， 低剂量和低剂量的癌症病因风险估计的机制模型 剂量率照射。 我们的方法使用模型系统，其中DNA损伤被检测为单个 链断裂、双链断裂、各种碱基损伤，以及其对 细菌的转化效率。DNA底物是质粒， SV4O微型染色体。电离辐射包括γ射线和 a粒子为了评估DNA损伤，我们将采用三种新的模型系统， 我们已经开发了。这些系统的设计意图是 专注于直接效应（DNA本身的电离），因为 与间接效应（DNA）相比，对这一过程的了解很少 溶剂自由基的损害）。这些模型系统涉及DNA的使用， 部分水合膜的形式，DNA与单电子的反应 氧化剂，以及以高度相关的形式使用DNA。 由于DNA损伤是在明确定义的条件下产生的， 可以根据速率常数对其进行定量描述， 寿命和簇大小。其结果将是更好地了解 通过能量沉积引入损伤的机制是成簇的 经过修饰，导致永久性产品，最终导致生物 和生理终点。

DESCRIPTION (PROVIDED BY APPLICANT):The unique aspect of the biologically significant DNA damage associated with ionizing radiation is that this damage is clustered. It is therefore qualitatively distinct from that produced by UV radiation, or chemicals such as alkylating agents. The long-term goals of this work are to clarify the radiation chemical mechanisms by which DNA damage is introduced by ionizing radiation and by which it may be processed, modified, or repaired. This provides a means to evaluate the ability of cellular systems to cope with this damage. Applications to human health include defining the causes of individual variation in radiosensitivity (for example the role of anti-oxidants in protecting against radiation damage) and the development of mechanistic models for risk estimation of cancer etiology by low dose and low dose rate exposures. Our approach uses model systems in which DNA damage is detected as single strand breaks, double strand breaks, various base damages, and by its effect on the transformation efficiency of bacteria. The DNA substrates are plasmids and the SV4O minichromosome. The ionizing radiations include 7-rays and a-particles. To assess DNA damage, we will employ three new model systems that we have developed. These systems have been designed with the intention of concentrating upon the direct effect (ionization of the DNA itself), because this process is poorly understood in comparison with the indirect effect (DNA damage by solvent radicals). These model systems involve the use of DNA in the form of partially hydrated films, the reaction of DNA with one-electron oxidants, and the use of DNA in a highly associated form. Because the DNA damage is produced under well-defined conditions, a quantitative description of it can be made in terms of rate constants, lifetimes, and cluster sizes. The result will be an improved understanding of the mechanisms by which damage is introduced by energy deposition, is clustered and modified, leads to permanent products, and ultimately leads to biological and physiological endpoints.