Involvement of telonomic instability in induction of delayed chromosome aberrations by ionizing radiation

电离辐射在受辐射细胞的后代中引起遗传不稳定。为了阐明氧化应激在电离辐射（IR）诱导遗传不稳定性易感性中的作用，我们在正常氧合（20%）和缺氧（2%）条件下检测了x射线诱导的人类胚胎细胞延迟染色体畸变。结果显示，低氧降低了延迟性染色体畸变，提示氧化应激在IR诱导遗传不稳定中起重要作用。为了了解DNA双链断裂（DBSs）修复过程在诱导遗传不稳定性中的作用，我们研究了x射线诱导的scid小鼠细胞的延迟染色体畸变，这种染色体畸变在DSBs的非同源末端连接修复中存在缺陷。染色体分析显示，scid细胞比野生型细胞更容易诱导延迟双中心染色体，即使它们接受相同的生存剂量。这一结果表明，dsb的修复受损可能是诱导遗传不稳定的高易感性的原因之一。为了了解延迟双中心染色体的形成机制，我们使用端粒- fish （t-FISH）技术检测了延迟双中心染色体中保留在两条染色体连接位置的端粒序列。结果表明，x辐射增强了端粒融合的诱导作用，其中t- FISH阳性信号保持在连接位置，并且scid细胞的端粒融合百分比高于野生型细胞。根据这些结果，我们提出延迟染色体畸变的诱导是由融合桥断裂（FBB）周期介导的，可能是由IR诱导的染色体不稳定引发的。

Ionizing radiation induces genetic instability in the progeny of irradiated cells. To elucidate the role of oxidative stress in the susceptibility to induction of genetic instability by ionizing radiation (IR), we examined X-ray-induced delayed chromosome aberrations in human embryo cells under normally oxygenated (20%) and hypoxic (2%) conditions. The results revealed that hypoxia reduced the delayed chromosome aberrations, suggesting that oxidative stress plays a significant role in the induction of genetic instability by IR.To know the role of repair process for DNA double-strand breaks (DBSs) in the induction of genetic instability, we studied X-ray-induced delayed chromosome aberrations in scid mouse cells, which defect in non-homologous end-joining repair for DSBs. The chromosome analysis revealed that scid cells were 2-fold more susceptible to the induction of delayed dicentric chromosomes than wild-type cells even though they received an equivalent survival dose. This result suggests that the impaired repair for DSBs might contribute to the high susceptibility to the induction of genetic instability. To know the mechanism for the formation of delayed dicentric chromosomes, we examined telomere sequences remained at the junctional position of two chromosomes in the delayed dicentric chromosomes using telomere-FISH (t-FISH) technique. The result showed that X-irradiation enhanced the induction of telomeric fusions where the t- FISH positive signals remained at the junctional position and also that the higher percentage of telomeric fusions in scid cells than in wild-type cells. From these results, we propose that the induction of delayed chromosome aberrations is mediated by fusion-bridge-breakage (FBB) cycle possibly initiated with telonomic instability induced by IR.