Ultrastructural Insights into the Biological Significance of Persisting DNA Damage Foci after Low Doses of Ionizing Radiation
Ultrastructural Insights into the Biological Significance of Persisting DNA Damage Foci after Low Doses of Ionizing Radiation
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DOI：
10.1158/1078-0432.ccr-15-3081
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发表时间：
2016-11-01
影响因子：
11.5
通讯作者：
Ruebe, Claudia E.
中科院分区：
文献类型：
--
作者：
Lorat, Yvonne;Schanz, Stefanie;Ruebe, Claudia E.
目的：调强放疗（IMRT）能够在不影响周围非靶向组织的情况下，向靶体积输送高剂量。然而，IMRT治疗大大增加了接受低剂量辐照的正常组织体积，但其生物学后果尚不清楚。实验设计：使用基因DNA修复能力不同的小鼠品系，我们研究了皮质神经元在每日低剂量（0.1 Gy）照射下的DNA损伤反应。利用光镜和电镜方法，我们列举并表征了DNA损伤灶作为双链断裂（DSBs）的标记。结果：在重复低剂量照射下，各组小鼠脑组织皮质神经元的持续灶均随剂量累积而显著增加，修复缺陷小鼠的大尺寸灶积累最为明显。电镜分析显示，修复熟练的神经元中持续的病灶反映了异染色质的染色质改变，而不是持续未修复的dsb。相比之下，修复缺陷的SCID神经元在eu-和异染色质中显示出大量未修复的DSB，这强调了DNA-PKcs在DSB重新连接中的基本作用，独立于染色质状态。在修复缺陷的ATM（-/-）神经元中，由于KAP1磷酸化受到干扰，大的持续损伤灶反映了多个未修复的dsb集中在异染色质边界。结论：反复低剂量照射可导致皮质神经元持续DNA损伤灶积累，对脑组织产生不良影响，增加致癌风险。多个未修复的dsb解释了修复缺陷神经元中较大的病灶，因此单独量化病灶可能低估了持续DNA损伤的程度和复杂性。(c) 2016年aacr。
Purpose: Intensity-modulated radiotherapy (IMRT) enables the delivery of high doses to target volume while sparing surrounding nontargeted tissues. IMRT treatment, however, substantially increases the normal tissue volume receiving low-dose irradiation, but the biologic consequences are unclear.Experimental Design: Using mouse strains that varied in genetic DNA repair capacity, we investigated the DNA damage response of cortical neurons during daily low-dose irradiation (0.1 Gy). Using light and electron microscopic approaches, we enumerated and characterized DNA damage foci as marker for double-strand breaks (DSBs).Results: During repeated low-dose irradiation, cortical neurons in brain tissues of all mouse strains had a significant increase of persisting foci with cumulative doses, with the most pronounced accumulation of large-sized foci in repair-deficient mice. Electron microscopic analysis revealed that persisting foci in repair-proficient neurons reflect chromatin alterations in heterochromatin, but not persistently unrepaired DSBs. Repair-deficient SCID neurons, by contrast, showed high numbers of unrepaired DSBs in eu- and heterochromatin, emphasizing the fundamental role of DNA-PKcs in DSB rejoining, independent of chromatin status. In repair-deficient ATM(-/-) neurons, large persisting damage foci reflect multiple unrepaired DSBs concentrated at the boundary of heterochromatin due to disturbed KAP1 phosphorylation.Conclusion: Repeated low-dose irradiation leads to the accumulation of persisting DNA damage foci in cortical neurons and thus may adversely affect brain tissue and increase the risk of carcinogenesis. Multiple unrepaired DSBs account for large-sized foci in repair-deficient neurons, thus quantifying foci alone may underestimate extent and complexity of persistent DNA damage. (C) 2016 AACR.