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Review
. 2013:2013:649747.
doi: 10.1155/2013/649747. Epub 2013 Mar 6.

Oxidized extracellular DNA as a stress signal in human cells

Aleksei V Ermakov  1 , Marina S Konkova, Svetlana V Kostyuk, Vera L Izevskaya, Ancha Baranova, Natalya N Veiko
Affiliations
Review

Oxidized extracellular DNA as a stress signal in human cells

Aleksei V Ermakov et al. Oxid Med Cell Longev. 2013.

Abstract

The term "cell-free DNA" (cfDNA) was recently coined for DNA fragments from plasma/serum, while DNA present in in vitro cell culture media is known as extracellular DNA (ecDNA). Under oxidative stress conditions, the levels of oxidative modification of cellular DNA and the rate of cell death increase. Dying cells release their damaged DNA, thus, contributing oxidized DNA fragments to the pool of cfDNA/ecDNA. Oxidized cell-free DNA could serve as a stress signal that promotes irradiation-induced bystander effect. Evidence points to TLR9 as a possible candidate for oxidized DNA sensor. An exposure to oxidized ecDNA stimulates a synthesis of reactive oxygen species (ROS) that evokes an adaptive response that includes transposition of the homologous loci within the nucleus, polymerization and the formation of the stress fibers of the actin, as well as activation of the ribosomal gene expression, and nuclear translocation of NF-E2 related factor-2 (NRF2) that, in turn, mediates induction of phase II detoxifying and antioxidant enzymes. In conclusion, the oxidized DNA is a stress signal released in response to oxidative stress in the cultured cells and, possibly, in the human body; in particular, it might contribute to systemic abscopal effects of localized irradiation treatments.

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Figures

Figure 1
Figure 1
The proposed mechanisms for the propagation of the stress signal from irradiated cells to bystander cells. In this scheme, the 8-oxo-dG serves as a model example of DNA lesion that turns DNA fragments into the stress signal; it should be noted that other types of DNA lesions may be recognized as well. The central player that ensures amplification of the signal in this cascade is the oxidative stress. The secondary oxidative stress evoked in intact bystander cells occurs after an interaction of the oxidized ecDNA with the receptors, or oxidized DNA sensors, that must be present on the surface or inside the bystander cells. One possible candidate for oxidized DNA sensor is toll-like receptor TLR9.
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