DNA Damage Response and Immune Defense: Links and Mechanisms

Abstract

DNA damage plays a causal role in numerous human pathologies including cancer, premature aging, and chronic inflammatory conditions. In response to genotoxic insults, the DNA damage response (DDR) orchestrates DNA damage checkpoint activation and facilitates the removal of DNA lesions. The DDR can also arouse the immune system by for example inducing the expression of antimicrobial peptides as well as ligands for receptors found on immune cells. The activation of immune signaling is triggered by different components of the DDR including DNA damage sensors, transducer kinases, and effectors. In this review, we describe recent advances on the understanding of the role of DDR in activating immune signaling. We highlight evidence gained into (i) which molecular and cellular pathways of DDR activate immune signaling, (ii) how DNA damage drives chronic inflammation, and (iii) how chronic inflammation causes DNA damage and pathology in humans.

Keywords: DNA damage; DNA damage response (DDR); chronic inflammation; immune defense; tumourigenesis.

FIGURE 1

DNA sensing and activation of immune signaling. Nuclear DNA damage is recognized by a set of diverse sensors including: the protein complex of replication protein A (RPA) detecting single-strand breaks, the Mre11-Rad50-Nbs1 (MRN) complex sensing double-strand breaks and the MutS proteins recognizing mismatched bases. Single-stranded endosomal DNA activates TLR9 signaling. TLR9 recruits the myeloid differentiation marker 88 (MyD88) inducing the transcription of nuclear factor kappa B (NF-κB) and/or IFN-regulatory factor (IRF) by engaging with TANK-binding kinase 1 (TBK1). Cytosolic DNA can be detected by diverse DNA sensors including: (A) Ku70 activating IRF response. (B) DNA-PK mediating IRF response through engaging with TBK1/STING. (C) MRE-11 inducing IFN response by initiating STING-dependant signaling. (D) The innate immune adaptor CARD9 activating NF-κB. (E) RNA polymerase III inducing NF-κB activation. (F) The DNA-dependent activator of IFN regulatory factors (DAI), the interferon gamma-inducible protein 16 (IFI16), the DExD/H-box helicase 41 (DDX41) and the cGMP-AMP synthase (cGAS), all activating IFN response through TBK1/STING signaling.

FIGURE 2

Model illustrating how DNA damage leads to the activation of innate immunity and how innate immunity causes in return DNA damage. The DNA damage response leads to apoptosis, transient cell cycle arrest or cellular senescence. Transient cell cycle arrest has a protective effect against tumourigenesis as it allows cells to accurately repair DNA damage before cell cycle progression. Cellular senescence can cause senescent cells to modify their tissue environment through the senescence-associated secretory phenotype (SASP) resulting in cytokine secretion that activates the innate immune system. The innate immune system can suppress tumourigenesis by clearing senescent cells with oncogene activation or chronic DNA damage. However, SASP can also cause tumourigenesis through cytokine signaling promoting the proliferation of tumor cells. The activation of innate immunity involves the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and can promote chronic inflammation. The generation of ROS/RNS by innate immunity and chronic inflammation promotes tumourigenesis through causing mutations in neighboring cells, thus triggering DNA damage, or impairing DDR.