Modulation of the DNA-damage response to HZE particles by shielding
Modulation of the DNA-damage response to HZE particles by shielding
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DOI：
10.1016/j.dnarep.2008.06.016
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发表时间：
2008-10-01
期刊：
影响因子：
3.8
通讯作者：
Burma, Sandeep
中科院分区：
文献类型：
--
作者：
Mukherjee, Bipasha;Camacho, Cristel Vanessa;Burma, Sandeep
高原子序数和高能量的离子(HZE粒子)对执行长时间太空任务的宇航员构成重大的癌症风险。在地球上，类似的离子正被用于靶向癌症治疗。这些粒子的性质在通过航天器屏蔽、治疗光束调制器或人体时可能会发生巨大变化。在这里，我们使用了对DNA双链断裂(DSB)的相关反应来了解铁离子在通过屏蔽或组织等效材料过程中的能量损失和核碎裂的后果。组蛋白H2AX的磷酸化和53BP1的募集被用来生成人类细胞DNA损伤的三维重建并跟踪其修复。人类细胞不能修复铁离子引起的DNA损伤的很大一部分。不同程度地需要DNA-PK和ATM来部分修复铁诱导的DNA损伤。铝屏蔽对DNA损伤或修复几乎没有影响，这证实了航天飞机和国际空间站的外壳对这些粒子几乎没有保护作用。另一方面，铅屏蔽由于粒子穿越过程中的能量损失而加剧了铁离子的影响。与之形成鲜明对比的是，聚乙烯(PE)是一种受欢迎的含氢屏蔽材料，它会导致DNA损伤，而这种损伤更容易修复，这可能是由于铁离子的碎裂。人类细胞确实能够有效地修复由代表铁的碎裂产物的氯离子和质子引起的DSB。有趣的是，在铁照射的细胞中，肿瘤抑制因子P53的激活是独特的双相，最终诱导高水平的p21(Waf1/Cip1)、p16(INK4a)和衰老相关的(β-半乳糖苷酶活性)。令人惊讶的是，即使在没有ATM激酶的情况下，这些事件也会发生，这意味着ATR可能是铁离子造成的复杂DNA损伤的主要反应。值得注意的是，通过PE的铁束的碎裂减弱了这些反应，这反过来在集落形成试验中导致了更好的长期存活率。我们的结果有助于我们理解离子碎裂通过材料产生的生物学后果，无论是在太空中还是在临床上，并为我们使用PE等含氢材料作为有效的空间屏蔽提供了生物学基础。(C)2008爱思唯尔B.V.保留所有权利。
Ions of high atomic number and energy (HZE particles) pose a significant cancer risk to astronauts on prolonged space missions. On Earth, similar ions are being used for targeted cancer therapy. The properties of these particles can be drastically altered during passage through spacecraft shielding, therapy beam modulators, or the human body. Here, we have used pertinent responses to DNA double-strand breaks (DSBs) to understand the consequences of energy loss versus nuclear fragmentation of Fe ions during passage through shielding or tissue-equivalent materials. Phosphorylation of histone H2AX and recruitment of 53BP1 were used to generate 3D reconstructions of DNA damage in human cells and to follow its repair. Human cells are unable to repair a significant portion of DNA damage induced by Fe ions. DNA-PK and ATM are required, to different extents, for the partial repair of Fe-induced DNA damage. Aluminum shielding has little effect on DNA damage or its repair, confirming that the hulls of the Space Shuttle and the International Space Station afford scant protection against these particles. Lead shielding, on the other hand, exacerbates the effects of Fe ions due to energy loss during particle traversal. In sharp contrast, polyethylene (PE), a favored hydrogenous shield, results in DNA damage that is more amenable to repair presumably due to Fe-ion fragmentation. Human cells are indeed able to efficiently repair DSBs induced by chlorine ions and protons that represent fragmentation products of Fe. Interestingly, activation of the tumor suppressor p53 in Fe-irradiated cells is uniquely biphasic and culminates in the induction of high levels of p21 (Waf1/Cip1), p16 (INK4a) and senescence-associated (beta-galactosidase activity. Surprisingly, these events occur even in the absence of ATM kinase implying that ATR may be a major responder to the complex DNA damage inflicted by Fe ions. Significantly, fragmentation of the Fe beam through PE attenuates these responses and this, in turn, results in better long-term survival in a colony-forming assay. Our results help us to understand the biological consequences of ion fragmentation through materials, whether in space or in the clinic, and provide us with a biological basis for the use of hydrogenous materials like PE as effective space shields. (c) 2008 Elsevier B.V. All rights reserved.