RADIATION-INDUCED ELECTRON MIGRATION IN NUCLEIC ACIDS

描述：细胞暴露在电离辐射下可导致长期 后果包括细胞死亡、转化和突变。 对导致DNA损伤的早期物理化学事件的研究是 对于实现对电离影响的机械性理解是必要的 细胞内的辐射。我们认为电子转移代表着一种 发生在多个受损地点的早期事件的重要组成部分 暴露于电离辐射后的DNA。在调查员最初的 他们的工作表明，辐射诱导的电子沿DNA的迁移是 控制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，研究人员证明了电子迁移既是 依赖于序列和构象，电子能够 沿DNA的短距离迁移和电子转移发生 优选在5‘至3’方向上。除了影响之外， 辐射损伤机制中的电子转移 发生在多个受损部位，了解电荷的机制 沿DNA的转移对于药物的基本设计具有临床意义 会影响细胞的辐射敏感性。以进一步阐明其作用机制 关于核酸中的电子转移，我们将：1)确定相对 能够沿DNA迁移的电子所占的比例 DNA，水化的初级层，还是散装水；2)确定 电子是否优先通过重叠迁移 --DNA：水复合体中堆积的碱基所产生的电子轨道； 3)研究电子是否能够进行线间迁移；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(S)；5)确定序列 体内和体外照射的DNA中电子迁移的特异性。 总体而言，研究人员的工作将阐明 电子沿DNA迁移以及物理化学和生化因素 这会影响到移民。这项工作将有助于更详细地 对辐射沉积机理的认识 DNA的多个损伤部位的损伤和BrdU的放射增敏。

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.