RADIATION INDUCED DNA DAMAGE AS A FUNCTION OF HYDRATION

染色体是理解细胞的一个重要目标。 电离辐射的影响。在染色体中的各种成分中， DNA分子是辐射损伤最关键的部位。这些类型 和产生大量的辐射诱导的DNA损伤 DNA直接电离产生的自由基(直接 作用)以及DNA与在 周围环境(间接影响)。有人建议说， 辐射产生的主要细胞内DNA损伤物种是 羟基自由基，一种大量的水自由基。这个概念很大程度上是基于 DNA在水体系中辐照的研究。然而，对于细胞DNA来说， 辐射诱导的损伤可能会受到 染色体，如构成很大一部分的水合水 我们的工作表明，细胞内DNA周围的水分子 DNA水合层中紧密结合的水分子 导致辐射引起的DNA损伤主要是通过转移 从这些水分子带入DNA的电荷；这是一种 不同于散装水照射后对DNA的损伤 (哦，e(aq-))。因为破坏DNA的机制不同于 水化水比散装水，干预策略即 完全依靠清除羟基自由基来修饰DNA损伤可能 在细胞中取得的成功有限。 这项建议的目标是确定机制和程度 DNA周围的水合水对辐射有贡献- 诱导DNA损伤。需要检验的假设是辐射诱导的 水合作用中最里面紧密结合的水分子的损伤 会导致DNA损伤，与造成的损伤无法区分 通过DNA的直接电离。第一，产品的种类和数量 辐射诱导的DNA损伤与剂量、水化程度、 DNA构象，以及氧的存在或不存在将被检查。 这项工作将通过研究其修饰效果来扩展。 硫醇对DNA损伤的类型和数量的影响 水合层中紧密结合的水分子，直接 DNA分子的电离，以及大量的水自由基。信息 从这些研究派生出来的可能对理解 电离辐射导致癌症、突变和细胞的机制 杀伤力，以及选择或设计新的辐射防护器，可以减少 辐射的有害影响或改善 放射治疗。

The chromosome is an important target in understanding the cellular effects of ionizing radiation. Of the various components in a chromosome, the DNA molecule is the most critical site for radiation damage. The types and quantities of radiation-induced DNA damage are produced from the sum Of the radicals generated from the direct ionization of the DNA (direct effect) and from reactions of the DNA with free radicals formed in the surrounding environment (indirect effect). It has been suggested that the primary intracellular DNA damaging species produced by radiation is the hydroxyl radical, a bulk water radical. This concept is based largely on studies of DNA irradiated in aqueous systems. However, for cellular DNA, radiation-induced damage can be influenced by other components of the chromosome, e.g. the waters of hydration which comprise a large portion of the water molecules that surround intracellular DNA- Our work suggests that the tightly bound water molecules of the DNA hydration layer contribute to radiation-induced DNA damage primarily via the transfer of charges from these water molecules into the DNA; a mechanism that is different from the induction of DNA damage after irradiation of bulk water (OH.,e(aq-)). Since the mechanism for damaging DNA is different for the hydration water than for the bulk water, interventional strategies that exclusively rely on scavenging hydroxyl radicals to modify DNA damage may have limited success in cells. It is the objective of this proposal to determine the mechanism and extent to which the water of hydration around the DNA contributes to radiation- induced DNA damage. The hypothesis to be tested is that radiation-induced damage in the innermost, tightly bound water molecules of the hydration layer can result in DNA damage that is indistinguishable from that caused by the direct ionization of DNA. First the types and quantities of radiation-induced DNA damage as a function of dose, degree of hydration, DNA conformation, and the presence or absence of oxygen will be examined. This work will then be extended by studying the modifying effects of thiols on the types and quantities of DNA damage that is derived from the tightly bound water molecules in the hydration layer, the direct ionization of the DNA molecule, and the bulk water radicals. Information derived from these studies may be important for understanding the mechanisms by which ionizing radiation causes cancer, mutations and cell lethality, and selecting or designing new radioprotectors that may reduce the deleterious effects of radiation or improve the outcome of radiotherapy.