Evidence for formation of DNA repair centers and dose-response nonlinearity in human cells
Evidence for formation of DNA repair centers and dose-response nonlinearity in human cells
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DOI：
10.1073/pnas.1117849108
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发表时间：
2012-01-10
影响因子：
11.1
通讯作者：
Costes, Sylvain V.
中科院分区：
文献类型：
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作者：
Neumaier, Teresa;Swenson, Joel;Costes, Sylvain V.
DNA“修复中心”的概念和辐射诱导灶(RIF)在人类细胞中的含义一直存在争议。RIF的特征是DNA损伤感知蛋白的局部募集，如P53结合蛋白(53BP1)。在这里，我们为维修中心的存在提供了强有力的证据。我们利用活体成像和RIF动力学的数学拟合表明，RIF诱发率随着辐射剂量的增加而增加，而RIF消失的速度则随着辐射剂量的增加而减少。我们发现，相隔1到2微米的多个DNA双链断裂(DSB)可以迅速聚集到修复中心。对诱导/分辨率的剂量依赖关系进行数学校正后，我们观察到在更高剂量下的绝对RIF产额要小得多：2GY照射后的RIF绝对量为15RIF/GY，而0.1GY照射后的RIF绝对量约为的RIF/GY。53BP1-GFP在人乳腺细胞中随时间推移的累积RIF计数证实了这些结果。目前使用的标准模型采用线性标度，从高剂量电离辐射到低剂量电离辐射推断癌症风险。然而，我们在如此远的距离上发现DSB集群，对电离辐射风险与剂量成正比的一般假设提出了相当大的怀疑，相反，我们提供了一种可以更准确地解决电离辐射风险剂量依赖关系的机制。
The concept of DNA "repair centers" and the meaning of radiation-induced foci (RIF) in human cells have remained controversial. RIFs are characterized by the local recruitment of DNA damage sensing proteins such as p53 binding protein (53BP1). Here, we provide strong evidence for the existence of repair centers. We used live imaging and mathematical fitting of RIF kinetics to show that RIF induction rate increases with increasing radiation dose, whereas the rate at which RIFs disappear decreases. We show that multiple DNA double-strand breaks (DSBs) 1 to 2 mu m apart can rapidly cluster into repair centers. Correcting mathematically for the dose dependence of induction/resolution rates, we observe an absolute RIF yield that is surprisingly much smaller at higher doses: 15 RIF/Gy after 2 Gy exposure compared to approximately 64 RIF/Gy after 0.1 Gy. Cumulative RIF counts from time lapse of 53BP1-GFP in human breast cells confirmed these results. The standard model currently in use applies a linear scale, extrapolating cancer risk from high doses to low doses of ionizing radiation. However, our discovery of DSB clustering over such large distances casts considerable doubts on the general assumption that risk to ionizing radiation is proportional to dose, and instead provides a mechanism that could more accurately address risk dose dependency of ionizing radiation.