H2A.X Phosphorylation in Oxidative Stress and Risk Assessment in Plasma Medicine

Figure 5

Synopsis of the current understanding of the molecular mechanisms of cold physical plasma effects and the γH2A.X induction in the DDR. A plasma jet generates ROS/RNS in the liquid phase around the cell ①. Aquaporins facilitate the limited ROS/RNS passage across the cell membrane ②. Plasma increases the cytosolic ROS concentration and exposes the cell to oxidative stress, which the intracellular antioxidant system senses ③. By activating mitogen-activated protein kinases (MAPK) and increasing the tumor suppressor protein p53, ROS lead to increased expression of the proapoptotic Bax and cold plasma-induced changes in the mitochondrial membrane potential initiating the intrinsic apoptosis pathway ④. Plasma-generated ROS also trigger ER stress, which forces mitochondrial disintegration and increased calcium ⑤. In contrast to plasma, UVB light generates ROS intra- and extracellularly. The direct target of UV and ionizing radiation is DNA. While UVB rays induce single-strand breaks (SSBs) ⑥, IR leads to double-strand breaks (DSBs) ⑦. The DNA damage response elements are PI3 kinases; ATR is associated with SSBs, ATM, and DNA-PKcs are associated with DSBs. All three kinases induce the phosphorylation of the nuclear H2A.X to γH2A.X ⑧. In the current understanding, the plasma-induced DDR, including the activation of PI3 kinases and H2A.X, is not a direct plasma effect on the DNA but rather a consequence of plasma-induced redox signaling and apoptosis ⑨.