RADIATION-INDUCED ELECTRON MIGRATION IN NUCLEIC ACIDS

描述：细胞暴露于电离辐射可导致长期 结果包括细胞杀伤、转化和诱变。 对导致DNA损伤的早期物理化学事件的研究 为了从机制上了解电离的影响， 细胞内的辐射 我们认为电子转移代表了 早期发生在多处受损地点事件的重要组成部分， 暴露于电离辐射后的DNA。 在调查员的初步报告中， 他们的工作表明，辐射诱导的电子沿沿着迁移是 是决定初始辐射损伤分布的重要因素。 用5-BrU作为分子探针研究模型DNA中的电子相互作用 系统，研究人员证明，电子迁移是两个 序列和构象依赖，电子能够 沿着沿着DNA短距离迁移， 优选在5 ′至3 ′方向上。 除了影响， 辐射损伤机制中的电子转移 发生在多处受损的地方，了解电荷的机制 沿着DNA转移对于药物的基本设计具有临床意义 影响细胞的辐射敏感性。 为了进一步阐明 我们将：1）确定核酸中电子转移的相对分子质量。 能够沿着DNA迁移的电子的比例， DNA，水合作用的初级层，或本体水; 2）确定 电子是否优先迁移通过重叠的 由DNA：水复合物中堆积的核碱基产生的_-电子轨道; 3)研究电子是否能够在链间迁移; 4） 确定电子是否能够转移出迁移 沿着DNA进入蛋白质的途径;和5）确定序列 在体外和体内辐射的DNA中电子迁移的特异性。 总的来说，研究人员的工作将揭示机制， 电子沿着DNA迁移，物理化学和生物化学因素 这影响了移民。 这项工作将有助于更详细地 了解辐射沉积的机理基础 DNA和BrdU放射增敏中多重损伤位点的损伤。

DESCRIPTION: Exposure of cells to ionizing radiation can lead to long term consequences including cell killing, transformation and mutagenesis. Studies of early physico-chemical events that contribute to DNA damage are necessary to achieve a mechanistic understanding of the effects of ionizing radiation in cells. We propose that electron transfer represents a significant component of early events occurring in multiply damaged sites in DNA following exposure to ionizing radiation. In the investigator's initial work they have shown that radiation-induced electron migration along DNA is an important factor governing distribution of initial radiation damage. Using 5-BrU as a molecular probe to study electron interactions in model DNA systems, the investigators demonstrated that electron migration is both sequence and conformation dependent, that electrons were capable of migrating short distances along DNA and that electron transfer occurred preferentially in the 5' to 3' direction. In addition to the influence of electron transfer in mechanisms underlying radiation-induced damage occurring in multiply damaged sites, understanding mechanisms of charge transfer along DNA has clinical relevance for the rationale design of agents that affect cellular radiosensitivity. To further elucidate the mechanisms of electron transfer in nucleic acids we will: 1) determine the relative proportion of electrons capable of migrating along DNA that originate within the DNA, the primary layer of hydration, or the bulk water; 2) determine whether electrons are preferentially migrating through the overlapping _-electron orbitals created by stacked nucleobases in the DNA:water complex; 3) investigate whether electrons are capable of interstrand migration; 4) determine whether electrons are capable of transferring out of the migration pathway(s) along DNA into proteins; and 5) determine the sequence specificity for electron migration in DNA irradiated in vitro and in vivo. Overall, the investigator's work will shed light on the mechanisms by which electrons migrate along DNA and the physico-chemical and biochemical factors that influence migration. This work will contribute to a more detailed understanding of the mechanistic basis underlying deposition of radiation damage in multiply damaged sites in DNA and BrdU radiosensitization.