Oxidized DNA induces an adaptive response in human fibroblasts

Abstract

Cell-free DNA (cfDNA) released from dying cells contains a substantial proportion of oxidized nucleotides, thus, forming cfDNA(OX). The levels of cfDNA(OX) are increased in the serum of patients with chronic diseases. Oxidation of DNA turns it into a stress signal. The samples of genomic DNA (gDNA) oxidized by Н2О2in vitro (gDNA(OX)) induce effects similar to that of DNA released from damaged cells. Here we describe the effects of gDNA(OX) on human fibroblasts cultivated in the stressful conditions of serum withdrawal. In these cells, gDNA(OX) evokes an adaptive response that leads to an increase in the rates of survival in serum starving cell populations as well as in populations irradiated at the dose of 1.2Gy. These effects are not seen in control populations of fibroblasts treated with non-modified gDNA. In particular, the exposure to gDNA(OX) leads to a decrease in the expression of the proliferation marker Ki-67 and an increase in levels of РСNА, a decrease in the proportion of subG1- and G2/M cells, a decrease in proportion of cells with double strand breaks (DSBs). Both gDNA(OX) and gDNA suppress the expression of DNA sensors TLR9 and AIM2 and up-regulate nuclear factor-erythroid 2 p45-related factor 2 (NRF2), while only gDNA(OX) inhibits NF-κB signaling. gDNA(OX) is a model for oxidized cfDNA(OX) that is released from the dying tumor cells and being carried to the distant organs. The systemic effects of oxidized DNA have to be taken into account when treating tumors. In particular, the damaged DNA released from irradiated cells may be responsible for an abscopal effects and a bystander mediated adaptive response seen in some cancer patients. These results indicate the necessity for the further study of the effects of oxidized DNA in both in vitro and in vivo systems.