The role of extracellular DNA (exDNA) in cellular processes

Figures & data

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

Table 1. Biological processes in which exDNA participates in eukaryotes

Biological process	exDNA type	Key molecules	Chemical or biological characteristics	Probable biological effect
Cell signaling	Associated with lipoprotein complexes	Receptors: STING, AIM-2 RIG-1, DAI, TLRs	High content of 8-oxodG	Second messengersExchange of informationbetween nucleus and cytoplasmintra- and intercellular
Oxidative stress	Oxidized	NF-κB, TNF α, IL-1, 2, 6 & 12NRF-2, adhesion molecules	High content of 8-oxodG	Keeping of homeostasis
Radio-adaptiveresponses	Oxidized andnon-oxidized	TLR-9, NF-κB	Receptor cell biology	Cell cycle arrestAnti-oxidative response
Immunity	Chromatin	TLR-9, PAMPs, HMGB1, ROS, PAD4, IL-26, LL-37, Pro inflammatory cytokines,	Citrullination of histones H3 and H4	NETs formation Antimicrobial activity
Coagulation	Nucleosome	FSAP, Factor XI– XII, HK, VWF, GPIbα	Presence of NETs, glycosaminoglycan and RNA	Activation of the cascade Thrombus formation Increased blood viscosity
Gene transference	Naked DNA Chromatin Oncosome Apoptotic bodies	TRL-9, NF-κB, cyclin D1	Susceptible receptor cell	Inheritable biological modifications Angiogenesis Metastasis and invasion Microchimerism Apoptosis
Gene amplification	small fragments	Transposase?	Presence of transposable gene elements	Gain of metabolic functions Genomic instability