GENETIC/ CYTOGENETIC INSTABILITY OF IONIZING RADIATION

与辐射照射有关的健康问题以致癌作用为中心 以及在剂量通常太低而不能 产生可测量的生物反应。定量，生物学相关 低剂量风险估计需要数据，但这最终需要 外推法由基本机制的知识指导。越来越多的 证据表明，研究的适当机制与以下能力有关： 电离辐射破坏哺乳动物基因组的稳定性。大多数此类数据涉及 显微镜下可见的染色体变化延迟出现，或 辐射暴露后的亚微观突变根据初步 数据显示，一个工作模型已经建立，以解释染色体 在不稳定的交界面上形成的不稳定性， 涉及染色体易位和倒位的断裂点。这一基本 概念允许关于不稳定过程的各种预测， 目前提案中所载的五个具体目标体现了这一点。 这些概念包括：1）染色体不稳定性导致 生产“非复杂”的交流，涉及几个 染色体作为同一重排的一部分; 2）倒位是最多的 经常发生不稳定事件; 3）不稳定应该是共同特征 辐射的细胞。该模型的潜在进一步影响是：4）， 不稳定的重排可能最终导致突变的获得， 远离断点本身的位点; 5）并且 易位和倒位可以通过转录调控基因， 沉默

Health concerns related to radiation exposure center on carcinogenesis and mutagenesis following doses that are typically too low to produce a measurable biological response. Quantitative, biologically relevant data is needed for low dose risk estimates, but this will ultimately require extrapolation guided by a knowledge of underlying mechanisms. There is mounting evidence that the appropriate mechanisms to study relate to the ability of ionizing radiations to destabilize the mammalian genome. Most such data relates to the delayed appearance of microscopically visible changes to chromosomes, or submicroscopic mutations following radiation exposure. Based on preliminary data presented, a working model has been constructed to explain chromosomal instability in terms of unstable junctions that can form at the interface of breakpoints involved in chromosome translocations and inversions. This basic concept allows for various predictions regarding the instability process that are represented by the five specific aims contained in the current proposal. These include the notions: 1) that chromosomal instability leads to the production of "non-reciprocally complex" exchanges that involve several chromosomes as part of the same rearrangement; 2) that inversions are the most frequent destabilizing event; 3) and that instability should be common feature of irradiated cells. Potential further implications of the model are: 4) that unstable rearrangements may ultimately lead to the acquisition of mutations at loci that are distantly removed from the breakpoints themselves; 5) and that translocations and inversions may inactivate genes via transcriptional silencing.