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Formation of γH2AX and pATM Foci in Human Mesenchymal Stem Cells Exposed to Low Dose-Rate Gamma-Radiation

1
A. Tsyb Medical Radiological Research Centre—Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, Koroleva 4, Obninsk 249030, Russia
2
State Research Center—Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Moscow 123098, Russia
3
Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow 119991, Russia
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Moscow Institute of Physics and Technology, Dolgoprudny 141700, Russia
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National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, Moscow 125284, Russia
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Emanuel Institute for Biochemical Physics, Russian Academy of Sciences, Moscow 119991, Russia
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Faculty of Biology, Lomonosov Moscow State University, GSP-1, Leninskie Gory, Moscow 119991, Russia
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Center for Innovative Radiological and Regenerative Technologies of the Ministry of Health of the Russian Federation, Koroleva 4, Obninsk 249030, Russia
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Institute of Cell Biophysics, Russian Academy of Sciences, Institutskaya St., 3, Pushchino 142290, Russia
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Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1N 6N5, Canada
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(11), 2645; https://doi.org/10.3390/ijms20112645
Received: 19 March 2019 / Revised: 21 May 2019 / Accepted: 23 May 2019 / Published: 29 May 2019
(This article belongs to the Collection Radiation Toxicity in Cells)
DNA double-strand breaks (DSB) are among the most harmful DNA lesions induced by ionizing radiation (IR). Although the induction and repair of radiation-induced DSB is well studied for acute irradiation, responses to DSB produced by chronic IR exposures are poorly understood, especially in human stem cells. The aim of this study was to examine the formation of DSB markers (γH2AX and phosphorylated kinase ATM, pATM, foci) in human mesenchymal stem cells (MSCs) exposed to chronic gamma-radiation (0.1 mGy/min) in comparison with acute irradiation (30 mGy/min) at cumulative doses of 30, 100, 160, 240 and 300 mGy. A linear dose-dependent increase in the number of both γH2AX and pATM foci, as well as co-localized γH2AX/pATM foci (“true” DSB), were observed after an acute radiation exposure. In contrast, the response of MSCs to a chronic low dose-rate IR exposure deviated from linearity towards a threshold model, for γH2AX, pATM foci and γH2AX/pATM foci, with an indication of a “plateau”. The state of equilibrium between newly formed DSB at a low rate during the protracted exposure time and the elimination of a fraction of DSB is proposed as a mechanistic explanation of the non-linear DSB responses following a low dose-rate irradiation. This notion is supported by the observation of the elimination of a substantial fraction of DSB 6 h after the cessation of the exposures. Our results demonstrate non-linear dose responses for γH2AX and pATM foci in human MSCs exposed to low dose-rate IR and showed the existence of a threshold, which may have implications for radiation protection in humans. View Full-Text
Keywords: DNA double-strand breaks; γH2AX; pATM; γ-radiation; low dose-rate; human mesenchymal stem cells DNA double-strand breaks; γH2AX; pATM; γ-radiation; low dose-rate; human mesenchymal stem cells
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Ulyanenko, S.; Pustovalova, M.; Koryakin, S.; Beketov, E.; Lychagin, A.; Ulyanenko, L.; Kaprin, A.; Grekhova, A.; M. Ozerova, A.; V. Ozerov, I.; Vorobyeva, N.; Shegay, P.; Ivanov, S.; Leonov, S.; Klokov, D.; Osipov, A.N. Formation of γH2AX and pATM Foci in Human Mesenchymal Stem Cells Exposed to Low Dose-Rate Gamma-Radiation. Int. J. Mol. Sci. 2019, 20, 2645.

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