Oncotarget

Research Papers:

γH2AX, 53BP1 and Rad51 protein foci changes in mesenchymal stem cells during prolonged X-ray irradiation

Anastasia Tsvetkova, Ivan V. Ozerov, Margarita Pustovalova, Anna Grekhova, Petr Eremin, Natalia Vorobyeva, Ilya Eremin, Andrey Pulin, Vadim Zorin, Pavel Kopnin, Sergey Leonov, Alex Zhavoronkov, Dmitry Klokov, Andreyan N. Osipov _

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Oncotarget. 2017; 8:64317-64329. https://doi.org/10.18632/oncotarget.19203

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Abstract

Anastasia Tsvetkova1, Ivan V. Ozerov2,3, Margarita Pustovalova2,4, Anna Grekhova2,4,5, Petr Eremin6, Natalia Vorobyeva2,3, Ilya Eremin6, Andrey Pulin6, Vadim Zorin6,7, Pavel Kopnin8, Sergey Leonov9, Alex Zhavoronkov3, Dmitry Klokov10 and Andreyan N. Osipov2,3,4,9

1Lomonosov Moscow State University, Moscow 119991, Russia

2State Research Center - Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency (SRC-FMBC), Moscow 123098, Russia

3Insilico Medicine, Inc, ETC, Johns Hopkins University, Baltimore, Maryland 21218, USA

4Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow 119991, Russia

5Emanuel Institute for Biochemical Physics, Russian Academy of Sciences, Moscow 119991, Russia

6Federal State Budgetary Institution “Central Clinical Hospital with Outpatient Health Center” of The Business Administration for The President of The Russian Federation, Moscow 121359, Russia

7PJSC Human Stem Cells Institute, Moscow 119333, Russia

8N.N. Blokhin Cancer Research Center, Moscow 115478, Russia

9Moscow Institute of Physics and Technology, Moscow 141700, Russia

10Canadian Nuclear Laboratories, Chalk River, Ontario K0J1P0, Canada

Correspondence to:

Andreyan N. Osipov, email: andreyan.osipov@gmail.com

Keywords: DNA double strand breaks, DNA repair, mesenchymal stem cells, X-rays, continuous irradiation

Received: December 02, 2016     Accepted: June 20, 2017     Published: July 12, 2017

ABSTRACT

At high exposure levels ionizing radiation is a carcinogen. Little is known about how human stem cells, which are known to contribute to tumorigenesis, respond to prolonged radiation exposures. We studied formation of DNA double strand breaks, accessed as γH2AX and 53BP1 foci, in human mesenchymal stem cells (MSCs) exposed to either acute (5400 mGy/h) or prolonged (270 mGy/h) X-irradiation. We show a linear γH2AX and 53BP1 dose response for acute exposures. In contrast, prolonged exposure resulted in a dose-response curve that had an initial linear portion followed by a plateau. Analysis of Rad51 foci, as a marker of homologous recombination, in cells exposed to prolonged irradiation revealed a threshold in a dose response. Using Ki67 as a marker of proliferating cells, we show no difference in the γH2AX distribution in proliferating vs. quiescent cells. However, Rad51 foci were found almost exclusively in proliferating cells. Concurrent increases in the fraction of S/G2 cells were detected in cells exposed to prolonged irradiation by scoring CENPF-positive cells. Our data suggest that prolonged exposure of MSCs to ionizing radiation leads to cell cycle redistribution and associated activation of homologous recombination. Also, proliferation status may significantly affect the biological outcome, since homologous repair is not activated in resting MSCs.


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