ATR signaling cooperates with ATM in the mechanism of low dose hypersensitivity induced by carbon ion beam
ATR signaling cooperates with ATM in the mechanism of low dose hypersensitivity induced by carbon ion beam
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DOI：
10.1016/j.dnarep.2015.07.001
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发表时间：
2015-10-01
期刊：
影响因子：
3.8
通讯作者：
Yu, Dong
中科院分区：
文献类型：
--
作者：
Xue, Lian;Furusawa, Yoshiya;Yu, Dong
中、高线性能量转移（LET）粒子辐照后，低剂量辐射超敏感（HRS）和随后出现的辐射抗性（IRR）的机制尚不清楚。本研究旨在探讨ATR通路是否参与高LET辐射诱导HRS的机制。用碳离子束辐照GM 0639细胞和两个ATM缺陷/突变细胞AT 5 BIVA和AT 2KY。胸苷阻断技术被开发用于富集G2期群体。采用双参数流式细胞术检测磷酸化组蛋白H3阳性细胞，定量评价放射诱导的早期G2/M检查点。在碳离子束照射前用特异性抑制剂预处理，检测ATR通路参与HRS/IRR反应。碳离子束下早期G2/M检查点与HRS/IRR之间的联系首先在GM 0639细胞中得到证实，通过富集G2期的细胞群或使用减弱G2向M期转变的Aurora激酶抑制剂。有趣的是，早期G2/M停滞仍然可以在ATM缺陷/突变细胞中观察到ATR信号传导的作用，这被发现以LET依赖的方式起作用，即使对于碳离子辐射低至0.2戈伊。ATR抑制剂对重粒子诱发的HRS/IRR的影响与ATM抑制剂相似，表明ATR通路参与了重粒子诱发的HRS/IRR的发生。提示ATR通路可能与ATM协同参与了碳离子束诱发低剂量超敏反应的机制。(C)2015爱思唯尔B. V.保留所有权利。
Little work has been done on the mechanism of low dose hyper-radiosensitivity (HRS) and later appeared radioresistance (termed induced radioresistance (IRR)) after irradiation with medium and high linear energy transfer (LET) particles. The aim of this study was to find out whether ATR pathway is involved in the mechanism of HRS induced by high LET radiation. GM0639 cells and two ATM deficient/mutant cells, AT5BIVA and AT2KY were irradiated by carbon ion beam. Thymidine block technique was developed to enrich the G2-phase population. Radiation induced early G2/M checkpoint was quantitatively assess with dual-parameter flow cytometry by detecting the cells positive for phospho-histone H3. The involvement of ATR pathway in HRS/IRR response was detected with pretreatment of specific inhibitors prior to carbon ion beam. The link between the early G2/M checkpoint and HRS/IRR under carbon ion beam was first confirmed in GM0639 cells, through the enrichment of cell population in G2-phase or with Aurora kinase inhibitor that attenuates the transition from G2 to M phase. Interestingly, the early G2/M arrest could still be observed in ATM deficient/mutant cells with an effect of ATR signaling, which was discovered to function in an LET-dependent manner, even as low as 0.2 Gy for carbon ion radiation. The involvement of ATR pathway in heavy particles induced HRS/IRR was determined with the specific ATR inhibitor in GM0639 cells, which affected the HRS/IRR occurrence similarly as ATM inhibitor. These data demonstrate that ATR pathway may cooperate with ATM in the mechanism of low dose hypersensitivity induced by carbon ion beam. (C) 2015 Elsevier B.V. All rights reserved.