Biologically Significant Damage in DNA

描述(申请人提供)：生物上的独特之处 与电离辐射相关的显著DNA损伤是这种损伤 是聚集在一起的。因此，它在性质上不同于紫外线产生的光。 辐射，或烷化剂等化学物质。这样做的长期目标是 工作是澄清辐射化学机制，DNA损伤是通过 通过电离辐射引入的，并可通过其进行处理、修改或 修好了。这提供了一种评估蜂窝系统能力的方法 应对这一损害。对人类健康的应用包括确定病因 辐射敏感性的个体差异(例如， 抗辐射损伤中的抗氧化剂)和发展 低剂量和低剂量肿瘤病因风险评估的机理模型 剂量率暴露。 我们的方法使用模型系统，在模型系统中，DNA损伤被检测为 链断裂、双链断裂、各种碱基损伤及其对 细菌的转化效率。DNA底物是质粒和 SV4O微染色体。电离辐射包括7射线和 A粒子。为了评估DNA损伤，我们将采用三个新的模型系统 我们已经开发了。这些系统的设计意图是 专注于直接影响(DNA本身的电离)，因为 与间接效应(DNA)相比，人们对这一过程知之甚少 溶剂基的破坏)。这些模型系统涉及DNA在 部分水合的薄膜，DNA与单电子的反应 氧化剂，以及高度相关形式的DNA的使用。 因为DNA损伤是在明确定义的条件下产生的，所以 可以用速率常数对其进行定量描述， 生命周期和集群大小。结果将是更好地理解 通过能量沉积引入损害的机制是聚集的。 和修饰，导致永久产品，并最终导致生物 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.