Low doses of X-rays induce prolonged and ATM-independent persistence of γH2AX foci in human gingival mesenchymal stem cells
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Andreyan N. Osipov1,2,3,4, Margarita Pustovalova1,2, Anna Grekhova1,5, Petr Eremin1, Natalia Vorobyova1,3, Andrey Pulin1, Alex Zhavoronkov4,6,7, Sergey Roumiantsev3,4,8, Dmitry Y. Klokov9, Ilya Eremin1
1State Research Center - Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency (SRC-FMBC), Moscow, Russia
2Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow, Russia
3Dmitry Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
4Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, Russia
5Emanuel Institute for Biochemical Physics, Russian Academy of Sciences, Moscow, Russia
6Insilico Medicine, Inc, ETC, Johns Hopkins University, Baltimore, Maryland, USA
7The Biogerontology Research Foundation, BGRF, London, UK
8N.I. Pirogov Russian National Research Medical University, Moscow, Russia
9Canadian Nuclear Laboratories, Chalk River, Ontario, Canada
Andreyan N. Osipov, e-mail: firstname.lastname@example.org
Keywords: mesenchymal stem cells, DNA double-strand breaks, DNA repair, X-rays, low doses
Received: April 08, 2015 Accepted: July 10, 2015 Published: July 23, 2015
Diagnostic imaging delivering low doses of radiation often accompany human mesenchymal stem cells (MSCs)-based therapies. However, effects of low dose radiation on MSCs are poorly characterized. Here we examine patterns of phosphorylated histone H2AX (γH2AX) and phospho-S1981 ATM (pATM) foci formation in human gingiva-derived MSCs exposed to X-rays in time-course and dose-response experiments. Both γH2AX and pATM foci accumulated linearly with dose early after irradiation (5–60 min), with a maximum induction observed at 30–60 min (37 ± 3 and 32 ± 3 foci/cell/Gy for γH2AX and pATM, respectively). The number of γH2AX foci produced by intermediate doses (160 and 250 mGy) significantly decreased (40–60%) between 60 and 240 min post-irradiation, indicating rejoining of DNA double-strand breaks. In contrast, γH2AX foci produced by low doses (20–80 mGy) did not change after 60 min. The number of pATM foci between 60 and 240 min decreased down to control values in a dose-independent manner. Similar kinetics was observed for pATM foci co-localized with γH2AX foci. Collectively, our results suggest differential DNA double-strand break signaling and processing in response to low vs. intermediate doses of X-rays in human MSCs. Furthermore, mechanisms governing the prolonged persistence of γH2AX foci in these cells appear to be ATM-independent.
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