Research Papers:

Low doses of X-rays induce prolonged and ATM-independent persistence of γH2AX foci in human gingival mesenchymal stem cells

Andreyan N. Osipov _, Margarita Pustovalova, Anna Grekhova, Petr Eremin, Natalia Vorobyova, Andrey Pulin, Alex Zhavoronkov, Sergey Roumiantsev, Dmitry Y. Klokov and Ilya Eremin

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Oncotarget. 2015; 6:27275-27287. https://doi.org/10.18632/oncotarget.4739

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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

Correspondence to:

Andreyan N. Osipov, e-mail: andreyan.osipov@gmail.com

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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