Abstract
BackgroundIonizing radiation (IR) can be extremely harmful for human cells since an improper DNA-damage response (DDR) to IR can contribute to carcinogenesis initiation. Perturbations in DDR pathway can originate from alteration in the functionality of the microRNA-mediated gene regulation, being microRNAs (miRNAs) small noncoding RNA that act as post-transcriptional regulators of gene expression. In this study we gained insight into the role of miRNAs in the regulation of DDR to IR under microgravity, a condition of weightlessness experienced by astronauts during space missions, which could have a synergistic action on cells, increasing the risk of radiation exposure.Methodology/Principal FindingsWe analyzed miRNA expression profile of human peripheral blood lymphocytes (PBL) incubated for 4 and 24 h in normal gravity (1 g) and in modeled microgravity (MMG) during the repair time after irradiation with 0.2 and 2Gy of γ-rays. Our results show that MMG alters miRNA expression signature of irradiated PBL by decreasing the number of radio-responsive miRNAs. Moreover, let-7i*, miR-7, miR-7-1*, miR-27a, miR-144, miR-200a, miR-598, miR-650 are deregulated by the combined action of radiation and MMG. Integrated analyses of miRNA and mRNA expression profiles, carried out on PBL of the same donors, identified significant miRNA-mRNA anti-correlations of DDR pathway. Gene Ontology analysis reports that the biological category of “Response to DNA damage” is enriched when PBL are incubated in 1 g but not in MMG. Moreover, some anti-correlated genes of p53-pathway show a different expression level between 1 g and MMG. Functional validation assays using luciferase reporter constructs confirmed miRNA-mRNA interactions derived from target prediction analyses.Conclusions/SignificanceOn the whole, by integrating the transcriptome and microRNome, we provide evidence that modeled microgravity can affects the DNA-damage response to IR in human PBL.
Highlights
Eukaryotic cells have evolved efficient DNA-damage response to genotoxic agents in order to eliminate any detrimental effect of DNA lesions
MicroRNA expression profiling was performed on total RNA extracted at the end of incubation times (Figure 1), by comparing the expression profile of irradiated vs. non-irradiated peripheral blood lymphocytes (PBL) of the same donor
Data obtained from PBL incubated in 1 g allowed to identify 26 (0.2Gy) and 20 (2Gy) radio-responsive miRNAs at 4 h after irradiation; miRNAs differentially expressed at 24 h after irradiation were 17 (0.2Gy) and 52 (2Gy), (Figure 2A and Table 1)
Summary
Eukaryotic cells have evolved efficient DNA-damage response to genotoxic agents in order to eliminate any detrimental effect of DNA lesions. Despite the abundance of data about the biological effects of space and simulated microgravity, it is still unclear whether microgravity can affects the DNA-damage response (DDR) to IR. The repair of radiation-induced DNA damage seems to be unaffected by microgravity in bacteria and human fibroblasts [30,31] and in yeast [32]. Ionizing radiation (IR) can be extremely harmful for human cells since an improper DNA-damage response (DDR) to IR can contribute to carcinogenesis initiation. In this study we gained insight into the role of miRNAs in the regulation of DDR to IR under microgravity, a condition of weightlessness experienced by astronauts during space missions, which could have a synergistic action on cells, increasing the risk of radiation exposure
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