Abstract
Complete and accurate DNA replication is essential to genome stability maintenance during cellular division. However, cells are routinely challenged by endogenous as well as exogenous agents that threaten DNA stability. DNA breaks and the activation of the DNA damage response (DDR) arising from endogenous replication stress have been observed at pre- or early stages of oncogenesis and senescence. Proper detection and signalling of DNA damage are essential for the autonomous cellular response in which the DDR regulates cell cycle progression and controls the repair machinery. In addition to this autonomous cellular response, replicative stress changes the cellular microenvironment, activating the innate immune response that enables the organism to protect itself against the proliferation of damaged cells. Thereby, the recent descriptions of the mechanisms of the pro-inflammatory response activation after replication stress, DNA damage and DDR defects constitute important conceptual novelties. Here, we review the links of replication, DNA damage and DDR defects to innate immunity activation by pro-inflammatory paracrine effects, highlighting the implications for human syndromes and immunotherapies.
Highlights
The maintenance of genome stability is essential to the accurate transmission of genetic information.genome instability is a hallmark of cancer cells [1]
SAMHD1-depleted cells, MRE11-dependent resection of stalled replication forks is replaced by the RecQ1 helicase unwinding of the DNA; by cleaving the DNA flap generated, an endonuclease generates single-stranded DNA (ssDNA) fragments that accumulate in the cytosol, where they activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)
BRCA1 plays a hitherto unidentified role as a cofactor to IFI16 in the nuclear innate sensing of foreign DNA and the subsequent assembly and cytoplasmic distribution of stable IFI16-inflammasomes leading to IL-1β formation, as well as the induction of IFN-β via cytoplasmic signalling through IFI16, STING, TBK1 and Interferon Regulatory Factor 3 (IRF3) [168]
Summary
The maintenance of genome stability is essential to the accurate transmission of genetic information. The DDR protects genome stability through the precise coordination of a network of pathways, ensuring faithful transmission of genetic material, including DNA replication, repair and recombination, cell cycle checkpoint and chromosome segregation. These autonomous cell responses induce senescence or cell death [21,22,23,24,25]. Syndromes caused by mutations in DDR and/or DNA repair factors are often associated with high genetic instability, cancer predisposition and premature ageing [24,26,27,28] In addition to these cell-autonomous responses, protective process(es) act at the organism level. We will discuss how replicative stress and DNA damage (mainly DNA double-strand breaks, DSBs) can activate innate immunity and the consequences for autoimmune diseases and immunotherapy
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