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

Clarissa S Schütz,Sander Bekeschus,Matthias B Stope,Antonello Lorenzini

doi:10.1155/2021/2060986

Abstract

At serine139-phosphorylated gamma histone H2A.X (γH2A.X) has been established over the decades as sensitive evidence of radiation-induced DNA damage, especially DNA double-strand breaks (DSBs) in radiation biology. Therefore, γH2A.X has been considered a suitable marker for biomedical applications and a general indicator of direct DNA damage with other therapeutic agents, such as cold physical plasma. Medical plasma technology generates a partially ionized gas releasing a plethora of reactive oxygen and nitrogen species (ROS) simultaneously that have been used for therapeutic purposes such as wound healing and cancer treatment. The quantification of γH2A.X as a surrogate parameter of direct DNA damage has often been used to assess genotoxicity in plasma-treated cells, whereas no sustainable mutagenic potential of the medical plasma treatment could be identified despite H2A.X phosphorylation. However, phosphorylated H2A.X occurs during apoptosis, which is associated with exposure to cold plasma and ROS. This review summarizes the current understanding of γH2A.X induction and function in oxidative stress in general and plasma medicine in particular. Due to the progress towards understanding the mechanisms of H2A.X phosphorylation in the absence of DSB and ROS, observations of γH2A.X in medical fields should be carefully interpreted.

Highlights

Since phosphorylated gamma histone H2A.X occurs rapidly, abundant, and stoichiometrically with the frequency of DNA double-strand breaks (DSBs), γH2A.X has proven itself as a recognized indicator for radiationinduced DSBs in particular and direct DNA damage in general [1]
Medical plasma technology generates a partially ionized gas releasing a plethora of reactive oxygen and nitrogen species (ROS) simultaneously that have been used for therapeutic purposes such as wound healing and cancer treatment
While the formation of DSB-related micronuclei as genotoxic markers correlates with the nuclear γH2A.X induction for ionizing and UVB radiation but not for cold plasma, plasma but not ionizing radiation (IR) or UVB-light-induced γH2A.X depends on redox-regulated signaling pathways, apoptosis, and caspase activation

Summary

Introduction

Since phosphorylated gamma histone H2A.X (γH2A.X) occurs rapidly, abundant, and stoichiometrically with the frequency of DNA double-strand breaks (DSBs), γH2A.X has proven itself as a recognized indicator for radiationinduced DSBs in particular and direct DNA damage in general [1]. Constitutive γH2A.X levels are cell line and treatment agent-dependent [87], and foci formation and spreading at DNA damage sites is not static but dynamic [99, 100] This is because foci expand over time so that many foci of lesser intensity generate approximately the same signal as a few intense ones. Because the response of eukaryotic cells to ionizing radiation is highly conserved and mediated by a DNA repair system characterized by early H2A.X phosphorylation, the γH2A.X foci detection is a wellestablished and sensitive assay to evaluate persistent DNA DSBs [70, 104]. Low-dose IR induces mitochondrial ROS production and metabolic oxidative stress (Figure 2) [113, 114] Both direct and indirect radiation effects initialize molecular signaling pathways that may repair the damage or culminate in base pair deletion, mutation, or cell death [115]. UV radiation raises ROS levels both extracellularly and intracellularly [59, 118], physical plasma influences the cellular redox equilibrium via exclusively exogenously generated ROS, subsequently exerting oxidative stress intracellularly [119]

Plasma Medicine

Findings

Conclusion