title: Low doses of X-rays induce prolonged and ATM-independent persistence of γH2AX foci in human gingival mesenchymal stem cells.
abstract: 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.
authors: State Research Center - Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency (SRC-FMBC), Moscow, Russia.|Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow, Russia.|Dmitry Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.|Moscow Institute of Physics and Technology, Dolgoprudny, Moscow, Russia.
authors: Andreyan N
authors: AN
authors: Osipov
authors: State Research Center - Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency (SRC-FMBC), Moscow, Russia.|Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow, Russia.
authors: Margarita
authors: M
authors: Pustovalova
authors: State Research Center - Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency (SRC-FMBC), Moscow, Russia.|Emanuel Institute for Biochemical Physics, Russian Academy of Sciences, Moscow, Russia.
authors: Anna
authors: A
authors: Grekhova
authors: State Research Center - Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency (SRC-FMBC), Moscow, Russia.
authors: Petr
authors: P
authors: Eremin
authors: State Research Center - Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency (SRC-FMBC), Moscow, Russia.|Dmitry Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
authors: Natalia
authors: N
authors: Vorobyova
authors: State Research Center - Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency (SRC-FMBC), Moscow, Russia.
authors: Andrey
authors: A
authors: Pulin
authors: Moscow Institute of Physics and Technology, Dolgoprudny, Moscow, Russia.|Insilico Medicine, Inc, ETC, Johns Hopkins University, Baltimore, Maryland, USA.|The Biogerontology Research Foundation, BGRF, London, UK.
authors: Alex
authors: A
authors: Zhavoronkov
authors: Dmitry Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.|Moscow Institute of Physics and Technology, Dolgoprudny, Moscow, Russia.|N.I. Pirogov Russian National Research Medical University, Moscow, Russia.
authors: Sergey
authors: S
authors: Roumiantsev
authors: Canadian Nuclear Laboratories, Chalk River, Ontario, Canada.
authors: Dmitry Y
authors: DY
authors: Klokov
authors: State Research Center - Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency (SRC-FMBC), Moscow, Russia.
authors: Ilya
authors: I
authors: Eremin
mesh_terms: D000328:Adult; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005881:Gingiva / Q000378:metabolism / Q000528:radiation effects*; D064368:Healthy Volunteers; D006657:Histones / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000528:radiation effects*; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D015398:Signal Transduction; D014965:X-Rays
chemical_list: C468783:H2AX protein, human; D006657:Histones; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: DNA double-strand breaks; DNA repair; X-rays; low doses; mesenchymal stem cells