The role of extracellular DNA (exDNA) in cellular processes

Abstract

Nowadays, extracellular DNA or circulating cell-free DNA is considered to be a molecule with clinical applications (diagnosis, prognosis, monitoring of treatment responses, or patient follow-up) in diverse pathologies, especially in cancer. Nevertheless, because of its molecular characteristics, it can have many other functions. This review focuses on the participation of extracellular DNA (exDNA) in fundamental processes such as cell signaling, coagulation, immunity, evolution through horizontal transfer of genetic information, and adaptive response to inflammatory processes. A deeper understanding of its role in each of these processes will allow development of better tools to monitor and control pathologies, as well as helping to generate new therapeutic options, beyond the applicability of DNA in liquid biopsy.

Keywords: Extracellular DNA; extracellular DNA traps; horizontal DNA transfer; oxidized DNA; second messenger DNA.

Figure 1.

Schematic representation of the cellular signaling pathways activated by oxidized exDNA (8-oxodG). The exDNA released by different mechanisms of cellular stress and cell damage, might be enriched with oxidized nucleotides, forming complexes with proteins and/or lipids. The 8-oxodG acting as DAMP (Damage-Associated Molecular Pattern) signal might easily enter into cells and interact with different PRRs (Patterns Recognition Receptors) such as STING, AIM-2, RIG-1 or DAI, and ROS (Reactive Oxygen Species) induces DDR (DNA Damage Response) responses

Figure 2.

Possible implications of exDNA in immune response. Bacteria, fungi and other opportunistic parasites might be recognized by the immune system cells such as macrophages and dendritic cells, and thus induce the release of pro-inflammatory cytokines as well as the generation of ROS (Reactive Oxygen Species). Several stimuli trigger the activation and set up of the NETs (Neutrophil Extracellular Traps), which involve the participation of several proteins such as PAD4, NF-kB and histones, that help in the construction of the DNA molecular network and to trap different pathogens. All this induces the participation of multiple immune cells, which ultimately leads to the death and elimination of exogenous microorganisms