Heat-Induced Perturbations of DNA Damage Signaling Pathways are Modulated by Molecular Chaperones
Heat-Induced Perturbations of DNA Damage Signaling Pathways are Modulated by Molecular Chaperones
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DOI：
10.1158/0008-5472.can-08-1639
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发表时间：
2009-03-01
期刊：
影响因子：
11.2
通讯作者：
Fleischer, Ilona
中科院分区：
文献类型：
--
作者：
Laszlo, Andrei;Fleischer, Ilona
热是已知最有效的放射增敏剂之一。多项随机试验表明，热疗是几种不同癌症部位放疗的良好辅助手段。然而，导致放射增敏的热和辐射相互作用的机制仍有待阐明。在本报告中，我们确定热量会引起细胞对电离辐射引起的 DNA 损伤的反应中一些最早事件的扰动。我们研究了热对热辐射细胞中含有 γ-H2AX/MDC1/53BP1 的复合物形成的影响。我们发现，这种复合物的形成在热辐射细胞中被延迟，以热但不依赖于辐射剂量的方式延迟。在耐热和热放射增敏抗性细胞中，热诱导的复合物形成延迟的长度减弱。 γ-H2AX/MDC1/53BP1 复合物形成的延迟长度与热放射增敏的程度相关，并受到分子伴侣 Hsc70 的调节。热放射增敏作用在 5313131 缺失细胞中减弱，这意味着 γ-H2AX/MDC1/53BP1 复合物形成的延迟在热放射增敏作用中发挥了作用。热量还导致 53BP1 下游 DNA 损伤反应事件的延迟。我们的结果支持这样的观点，即细胞对电离辐射引起的 DNA 损伤的反应的最早事件中热引起的扰动在热放射增敏中发挥作用。 [癌症研究 2009;69(5):2042-9]
Heat is one of the most potent radiosensitizers known. Several randomized trials have shown that hyperthermia is a good adjuvant for radiotherapy at several different cancer sites. However, the mechanism(s) involved in the interaction of heat and radiation that lead to radiosensitization remain to be elucidated. In this report, we have determined that heat induces perturbations in some of the earliest events in the cellular response to DNA damage induced by ionizing radiation. We studied the effect of heat on the formation of complexes containing gamma-H2AX/MDC1/53BP1 in heated-irradiated cells. We found that the formation of this complex was delayed in heated-irradiated cells, in a heat but not radiation dose-dependent manner. The length of the heat-induced delay of complex formation was attenuated in thermotolerant and heat radiosensitization-resistant cells. The length of the delay of gamma-H2AX/MDC1/53BP1 complex formation correlated with the magnitude of heat radiosensitization and was modulated by the molecular chaperone Hsc70. Heat radiosensitization was attenuated in 5313131-null cells, implying that the delay of the formation of the gamma-H2AX/MDC1/53BP1 complex plays a role in heat radiosensitization. Heat also induced a delay of events in the DNA damage response that are downstream from 53BP1. Our results support the notion that heat-induced perturbations in the earliest events of the cellular response to ionizing radiation-induced DNA damage play a role in heat radiosensitization. [Cancer Res 2009;69(5):2042-9]