DNA damage: a trigger of innate immunity but a requirement for adaptive immune homeostasis

Publisher Website
Google Scholar
Abstract
DNA double-stranded break (DSB) damage activates ataxia-telangiectasia mutated (ATM)-dependent cell-cycle checkpoints, leading to cell-cycle arrest and efficient DNA repair. The DNA DSB damage is repaired mainly by the non-homologous end-joining pathway in mammalian cells. Viral infection induces DNA-damage responses to DSBs that arise in infected host cells. These DNA-damage responses are required for the survival of host cells, but they can have either a positive or a negative effect on productive infection, depending on the type of virus. DNA-damage responses activate innate immune responses through several pathways, including the upregulation of expression of NKG2D (natural killer group 2, member D) ligands and interferon-regulatory factors. DNA DSBs are necessary intermediates of V(D)J recombination. They are required for generation of the large repertoire of antigen-specific cells that are the main components of the adaptive arm of the immune system. DNA-damage responses to DSBs have important roles in efficient V(D)J recombination and in prevention of recombination-activating gene (RAG)-protein-induced genetic instability in lymphocytes. Activation-induced cytidine deaminase (AID)-induced DNA lesions are required for both class-switch recombination and somatic hypermutation. DNA-damage responses to DSBs are important for class-switch recombination but dispensable for somatic hypermutation. Granzyme A and granzyme C are released by cytotoxic T lymphocytes and induce caspase-independent apoptosis of target cells, by activating pathways that introduce DNA DSBs into the genome of these cells.