Mechanistic link between DNA damage sensing, repairing and signaling factors and immune signaling

Abstract

Previously, DNA damage sensing, repairing and signaling machineries were thought to mainly suppress genomic instability in response to genotoxic stress. Emerging evidence indicates a crosstalk between DNA repair machinery and the immune system. In this chapter, we attempt to decipher the molecular choreography of how factors, including ATM, BRCA1, DNA-PK, FANCA/D2, MRE11, MUS81, NBS1, RAD51 and TREX1, of multiple DNA metabolic processes are directly or indirectly involved in suppressing cytosolic DNA sensing pathway-mediated immune signaling. We provide systematic details showing how different DDR factors' roles in modulating immune signaling are not direct, but are rather a consequence of their inherent ability to sense, repair and signal in response to DNA damage. Unexpectedly, most DDR factors negatively impact the immune system; that is, the immune system shows defective signaling if there are defects in DNA repair pathways. Thus, in addition to their known DNA repair and replication functions, DDR factors help prevent erroneous activation of immune signaling. A more precise understanding of the mechanisms by which different DDR factors function in immune signaling can be exploited to redirect the immune system for both preventing and treating autoimmunity, cellular senescence and cancer in humans.

Keywords: DDR; Genomic instability; Innate immunity; MRE11; Micronuclei; NBS1; RAD51; STING; Senescence; cGAS.

Fig. 1

Schematics show different stages of non-homologous end-joining, homologous recombination, base damage and replication stress processing pathways and the corresponding factors involved during various steps of these DNA metabolic pathways. Defects associated with any one of these factors will cause aging, immune disorder (immune) or cancer. FA, Fanconi anemia pathway factors; WRN, Werner syndrome protein; Polβ, DNA polymerase beta.

Fig. 2

Schematics show the mechanism of initiation and maintenance of immune signaling in cells defective for DNA sensing, repairing and signaling factors (DDR). Excessive processing of newly replicated genome by nucleases, normal DNA replication and DNA repair or defective G₂/M checkpoint followed by cytokinesis in cells defective in DDR factor result in the accumulation of self-DNA in the cytosol, fragmented DNA in the nucleus transported to cytosol and accumulation of chromatin fragments in the cytosol, respectively. Subsequently, cytosolic DNA sensing cGAS-STING-TBK1-IRF3 pathway initiates expression of immune genes, culminating in the establishment of aging, immune disorder or cancer.