GENETIC/ CYTOGENETIC INSTABILITY OF IONIZING RADIATION

与辐射暴露有关的健康问题集中在致癌上 和诱变后的剂量通常太低， 产生可测量的生物反应。定量的，与生物相关的 低剂量风险评估需要数据，但这最终需要 由对潜在机制的知识指导的外推。有越来越多的人 有证据表明，适当的研究机制与 电离辐射破坏哺乳动物基因组的稳定。大多数这样的数据都与 延迟出现显微镜下可见的染色体变化，或者 辐射暴露后的亚微观突变。基于初步的 给出的数据，已经构建了一个工作模型来解释染色体 在界面处形成的不稳定结的不稳定性 涉及染色体易位和倒位的断点。这是基本的 概念允许关于不稳定过程的各种预测 由本提案中所载的五个具体目标代表。 这些观点包括：1)染色体不稳定导致 产生“非互惠复杂的”交易，涉及几个 染色体作为同一重排的一部分；2)倒位是最多的 频繁发生破坏稳定事件；3)不稳定应该是共同特征 受过辐射的细胞。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获得突变 远离断点本身的基因座；5)以及 易位和倒位可能通过转录失活基因 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.