Residual γH2AX foci induced by low dose x-ray radiation in bone marrow mesenchymal stem cells do not cause accelerated senescence in the progeny of irradiated cells

Abstract

Mechanisms underlying the effects of low-dose ionizing radiation (IR) exposure (10-100 mGy) remain unknown. Here we present a comparative study of early (less than 24h) and delayed (up to 11 post-irradiation passages) radiation effects caused by low (80 mGy) vs intermediate (1000 mGy) dose X-ray exposure in cultured human bone marrow mesenchymal stem cells (MSCs). We show that γН2АХ foci induced by an intermediate dose returned back to the control value by 24 h post-irradiation. In contrast, low-dose irradiation resulted in residual γН2АХ foci still present at 24 h. Notably, these low dose induced residual γН2АХ foci were not co-localized with рАТМ foci and were observed predominantly in the proliferating Кi67 positive (Кi67+) cells. The number of γН2АХ foci and the fraction of nonproliferating (Кi67-) and senescent (SA-β-gal+) cells measured at passage 11 were increased in cultures exposed to an intermediate dose compared to unirradiated controls. These delayed effects were not seen in the progeny of cells that were irradiated with low-dose X-rays, although such exposure resulted in residual γН2АХ foci in directly irradiated cells. Taken together, our results support the hypothesis that the low-dose IR induced residual γH2AХ foci do not play a role in delayed irradiation consequences, associated with cellular senescence in cultured MSCs.

The p53–53BP1-Related Survival of A549 and H1299 Human Lung Cancer Cells after Multifractionated Radiotherapy Demonstrated Different Response to Additional Acute X-ray Exposure

“…Many studies suggest that DNA DSB repair is more efficient in cells that have survived repeated X-ray irradiation [34]. The histone variant H2AX phosphorylated at DSB sites by several protein kinases (ATM, ATR, and DNA-PK) called γH2AX is the most widely used marker of DNA DSBs [35][36][37]. ATM (ataxia telangiectasia mutated) is a major kinase that phosphorylates H2AX in response to IR-induced DNA damage [38,39].…”

Vive la radiorésistance!: converging research in radiobiology and biogerontology to enhance human radioresistance for deep space exploration and colonization

“…after the exposure to IR [ 151 , 191 , 195 – 199 ]. Moreover, markers specific to the particular DNA repair mechanisms (RAD51, Ku70/80, ATM) may be of a particular interest, as numerous studies have shown higher error-proneness of non-homologous end joining compared to the homologous recombination [ 29 , 30 , 36 , 200 – 202 ]. Application of the comprehensive multi-omics analytical tools on transcriptomic and proteomic data may serve as another useful approach for the individual radioresistance assessment [ 203 – 206 ].…”

Mesenchymal Stem Cells Early Response to Low-Dose Ionizing Radiation

“…On the other hand, it was shown that MSCs are sensitive to very low levels of radiation and trigger senescence due to impaired autophagy and DNA repair capacity (Alessio et al, 2015). Other authors confirm that the small radiation doses induce unrepaired double-strand breaks in MSCs (Osipov et al, 2015;Pustovalova et al, 2017;Ulyanenko et al, 2019). The authors of one of the articles conducted a comprehensive analysis of time-and dosedependent patterns of gene expression in a human MSC line exposed to IR (Jin et al, 2008).…”