Nucleic Acid Immunity and DNA Damage Response: New Friends and Old Foes

Abstract

The maintenance of genomic stability in multicellular organisms relies on the DNA damage response (DDR). The DDR encompasses several interconnected pathways that cooperate to ensure the repair of genomic lesions. Besides their repair functions, several DDR proteins have emerged as involved in the onset of inflammatory responses. In particular, several actors of the DDR have been reported to elicit innate immune activation upon detection of cytosolic pathological nucleic acids. Conversely, pattern recognition receptors (PRRs), initially described as dedicated to the detection of cytosolic immune-stimulatory nucleic acids, have been found to regulate DDR. Thus, although initially described as operating in specific subcellular localizations, actors of the DDR and nucleic acid immune sensors may be involved in interconnected pathways, likely influencing the efficiency of one another. Within this mini review, we discuss evidences for the crosstalk between PRRs and actors of the DDR. For this purpose, we mainly focus on cyclic GMP-AMP (cGAMP) synthetase (cGAS) and Interferon Gamma Inducible Protein 16 (IFI16), as major PRRs involved in the detection of aberrant nucleic acid species, and components of the DNA-dependent protein kinase (DNA-PK) complex, involved in the repair of double strand breaks that were recently described to qualify as potential PRRs. Finally, we discuss how the crosstalk between DDR and nucleic acid-associated Interferon responses cooperate for the fine-tuning of innate immune activation, and therefore dictate pathological outcomes. Understanding the molecular determinants of such cooperation will be paramount to the design of future therapeutic approaches.

New Insights in the Interplay Between African Swine Fever Virus and Innate Immunity and Its Impact on Viral Pathogenicity

“…While the mechanisms of regulation and inhibition of cGAS have been extensively studied in humans ( Hertzog and Rehwinkel, 2020 ; Taffoni et al, 2021 ), less is known about these mechanisms in pigs and other livestock species. For instance, it is unknown whether cGAS binds directly to ASFV genomes in cytoplasmic viral factories; in the nucleus, where early genome replication occurs ( Simões et al, 2019 ); or in other subcellular compartments, where cGAS can also be detected ( de Oliveira Mann and Hopfner, 2021 ).…”

Type-I Interferon Signaling in Fanconi Anemia

“…During the last decade, a series of studies have demonstrated the complex intertwined relationship between DNA repair processes and immune responses. One key signaling axis involved in this association is the type-I Interferon (IFN-I) response known to play a critical role in the antiviral response (Taffoni et al, 2021). IFN-I response is essential to induce the transcription of genes involved in DNA repair and in nucleic acid degradation.…”

“…IFN-I response is essential to induce the transcription of genes involved in DNA repair and in nucleic acid degradation. Therefore, in the presence of defects in DNA repair processes or nucleic acid metabolism, cellular immune receptors can be activated by self-nucleic acids (Taffoni et al, 2021). Given that new evidence suggests that loss of function of FA proteins causes IFN-I production (Bregnard et al, 2016;Reislander et al, 2019;Heijink et al, 2019), this review explores how defect in the FA pathway might contribute to the accumulation of cytosolic nucleic acids and activation of IFN-I (Figure 2).…”

Nucleic Acid Sensing Pathways in DNA Repair Targeted Cancer Therapy

“…Even if DNA damage does not directly kill cells, increasing evidence indicates that the accumulation of nucleic acids in the cytoplasm caused by DNA damage can also trigger an inflammatory response within the cells ( Nastasi et al, 2020 ). DNA damage-induced cytosolic nucleic acid shares common receptors (pattern recognition receptors, PRRs) and downstream effectors with those induced by viral or bacterial infections ( Takeuchi and Akira, 2010 ; Taffoni et al, 2021 ), which are summarized below ( Figure 1 ). And some agonists of these nucleic acid-sensing pathways are already in clinical trials ( Table 1 ).…”