Heat-induced perturbations of DNA damage signaling pathways are modulated by molecular chaperones.
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 53BP1-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.
Laszlo
Andrei
A
Division of Radiation and Cancer Biology, Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri 63108, USA. laszlo@wustl.edu
Fleischer
Ilona
I
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D050883:HSC70 Heat-Shock Proteins / Q000502:physiology; D006657:Histones / Q000378:metabolism; D006358:Hot Temperature; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D018832:Molecular Chaperones / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000378:metabolism; D011836:Radiation Tolerance; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C468783:H2AX protein, human; D050883:HSC70 Heat-Shock Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C413163:MDC1 protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C498301:TP53BP1 protein, human; D015534:Trans-Activators; D000071857:Tumor Suppressor p53-Binding Protein 1