When DNA-damage responses meet innate and adaptive immunity

Abstract

When cells proliferate, stress on DNA replication or exposure to endogenous or external insults frequently results in DNA damage. DNA-Damage Response (DDR) networks are complex signaling pathways used by multicellular organisms to prevent DNA damage. Depending on the type of broken DNA, the various pathways, Base-Excision Repair (BER), Nucleotide Excision Repair (NER), Mismatch Repair (MMR), Homologous Recombination (HR), Non-Homologous End-Joining (NHEJ), Interstrand Crosslink (ICL) repair, and other direct repair pathways, can be activated separately or in combination to repair DNA damage. To preserve homeostasis, innate and adaptive immune responses are effective defenses against endogenous mutation or invasion by external pathogens. It is interesting to note that new research keeps showing how closely DDR components and the immune system are related. DDR and immunological response are linked by immune effectors such as the cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway. These effectors act as sensors of DNA damage-caused immune response. Furthermore, DDR components themselves function in immune responses to trigger the generation of inflammatory cytokines in a cascade or even trigger programmed cell death. Defective DDR components are known to disrupt genomic stability and compromise immunological responses, aggravating immune imbalance and leading to serious diseases such as cancer and autoimmune disorders. This study examines the most recent developments in the interaction between DDR elements and immunological responses. The DDR network's immune modulators' dual roles may offer new perspectives on treating infectious disorders linked to DNA damage, including cancer, and on the development of target immunotherapy.

Keywords: Adaptive immunity; DNA-damage response (DDR); IFN; Innate immunity; cGAS–STING.

Fig. 1

Schematic diagram of DNA-damage response pathways. The integrity of the genome is constantly challenged by genotoxic factors (e.g., inheritance, endogenous reactive oxygen species, DNA replication stresses, or topoisomerase poisons) or exogenous insults (e.g., genotoxic drugs, irradiation, environmental pollutions, or pathogens invasion) that inducing DNA-damage. Accumulation of damaged DNA consequently induces genomic instability. The intricate pathways have been characterized for identifying and repairing DNA damage, summarized as the DNA-damage response (DDR). Overall, at least six distinct pathways may be activated solely or combinedly to repair DNA damage depending on the types of broken DNA, which are base-excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), double-strand breaks (DSBs) repair including homologous recombination (HR) and non-homologous end-joining (NHEJ), interstrand crosslink (ICL) repair and direct repair pathways. Intriguingly, although numerous genes are involved in the multiple complex processes of DDR, some common schedules are shared among diverse repair pathways

Fig. 2

DDR components regulate IFNs signaling pathways. The cellular innate immune response frequently intimately communicates with DDR components via DNA sensors-dependent IFNs signaling pathways. In the IFNs pathways, many DDR components regulate the initial sensing process by interacting with cGAS. cGAS is the universal dsDNA sensor that catalyzes the formation of cGAMP and comprises a heterocomplex with cGAMP to signal the cytosolic adaptor STING activation, which subsequently initiates IFN-1 production, inflammation response, or programmed cell death pathways. Several DDR components also participate in the STING and its downstream signaling pathways. Except for cGAS, other cytosolic DNA sensors like the DDX family, DAI, or IFI16 have also been found to associate with DDR components. Moreover, considering the nuclear location of cGAS, certain DDR components may interact with cGAS inside the cell nucleus, which indicates a potential role of cGAS in regulating the DNA-damage repairing process

Fig. 3

DDR components regulate cytosolic RNA sensors-dependent IFNs and NF-κB signaling pathways. The cytosolic RNA sensors (e.g., RIG-I and MDA5) signal to MAVS (also known as IPS-1, VISA, and Cardif) and induce IFN-I production or NF-κB activation through the TBK1-IRF3/7 signaling pathway. To date, The cellular innate immune responses also have been implicated under the control of DDR components via RNA sensors-dependent IFNs or NF-κB signaling pathways. For example, the RIG-I or RNA polymerase III responds to mtRNA or viral-derived 5′-pppRNA in the context of DNA damage

Fig. 4

DDR components regulate NF-κB signaling pathways. Although a few DDR components have been elucidated to be involved in the NF-κB signaling pathway, the inflammation response is extensively activated in the DNA-damage repairing process. Therefore, the specific roles of DDR components in NF-κB signaling pathway may be explored in the future

Fig. 5

DDR components regulate JAK-STAT signaling pathways. After attachment of IFNs to its cell membrane receptors IFNAR1 or IFNAR2, the cytoplasmic domains of IFNAR1 and IFNAR2 enable the trans-phosphorylation of tyrosine kinase 2 (Tyk2, one member of JAK tyrosine kinases) and JAK1. As phosphorylases, JAK1 phosphorylates STAT1/STAT2 to facilitate them forming a heterocomplex with IRF9, the IFN-stimulated gene factor 3 (ISGF3) complex. After that, the ISGF3 translocates into the nuclei and combines the IFN-stimulated response element (ISRE) to induce ISG expression. To date, the FEN1, FANC1, BLM, or FANCD have been elucidated to participate in JAK-STAT signaling pathways. Compared to immune sensors, the JAK/STAT axis mainly functions as an effector of DNA-damage-induced immune response

Fig. 6

DDR participates in T/B cell development and the stimulation of bone-marrow-derived cells. (1) DDR is essential to the basic development of B and T-lymphocytes. During the developing process, programmed genome alterations such as chromosomal V(D)J recombination, class-switch recombination (CSR), and somatic hyper-mutation (SHM) appear to generate diverse immunoglobulin (Ig) and T-cell receptor (TCR). (2) DDR may also be ignited in activated macrophages due to the production of reactive oxygen intermediates (ROIs) and reactive nitrogen intermediates (e.g., nitric oxide, NO)