Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

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.Genes 2020, 11, 409 2 of 26 formed when nascent transcripts re-anneal to their template DNA, displacing the non-template strand as single-stranded DNA (ssDNA) [12]. Elevated R-loop levels cause DNA damage and genome instability. The loss of RNA processing and regulatory factors increases R-loop levels, causing R-loop dependent DNA damage in eukaryotic cells [13][14][15][16].DNA breaks and activation of the DNA damage response (DDR), arising from endogenous replication stress, have been observed at early or precancerous stages, and adaptation to replication stress plays an important role in tumour development [17][18][19][20]. 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. Ultimately, these autonomous cell responses induce senescence or cell death [21][22][23][24][25]. All these processes prevent the proliferation of cells bearing DNA damage and/or genetic rearrangements. In agreement, 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) also act at the organism level. Such mechanism(s) involve the modification of the cellular microenvironment and ultimately the activation of innate immunity.The inflammatory response is a universal cell-intrinsic response to infections or tissue damage. Inflammation, which is triggered when innate immune cells detect infection, for example, eliminates the initial cause of cell injury, clears out necrotic cells and tissues damaged from the original insult and from the inflammatory process, and initiates ...

When STING Meets Viruses: Sensing, Trafficking and Response

“…After the invasion, viral PAMPs stimulate IFN production in a variety of cells, which possess a broad-spectrum antiviral effect ( 21 ). Thus, they would induce antiviral albumin to block viral propagation ( 22 ). For innate immune responses to viral invasion, although PRRs and IFN signaling are constituently components in nearly all somatic cells to control early infections in our body, it is believed that leukocytes are the protagonists in the stage to clear propagating viruses, by either secreted IFNs, and cytokines or cell killing.…”

Protective Mechanisms Against DNA Replication Stress in the Nervous System

“…Replication stress may generate genomic instability in the developing nervous system, and the importance of the replication stress response (RSR) pathways for the CNS formation has been demonstrated by many studies [13][14][15][16][17][18]. In addition, evidence that the RSR alters the cellular microenvironment and regulates immune responses has also accumulated rapidly [19,20]. Interestingly, recent research indicates that this non-cell-autonomous arm of the RSR may also contribute to the progression of neurodegenerative diseases [21].…”

“…As previously characterized for other subdivisions of DDR, the cellular responses to replication stress are diverse and may be subdivided into local and global responses. Local responses are the mechanisms that take place at the replication forks, whereas global responses include pan-nuclear and cytoplasmic processes, as well as functional responses that regulate the cellular microenvironment [19,68]. The stabilization of stalled forks, promotion of fork restarts, and regulation of origin firing are examples of processes that directly regulate replication forks or dormant origins.…”

“…In addition to these autonomous cellular responses, it is now well-documented that replication stress may also induce dramatic alterations in the cellular microenvironment. This non-cell-autonomous paracrine arm of RSR occurs through the regulation of proinflammatory cytokines [19,80]. In fact, a series of elegant studies provided evidence for replication stress-induced inflammation as a driver of neuronal degeneration in models of ataxia telangiectasia.…”

“…In addition to cell-autonomous mechanisms activated by RSR, it is now clear that replication stress may also induce alterations in the cellular microenvironment. The disruption of replication forks and/or DNA repair processes may induce the accumulation of cytoplasmic DNA (either dsDNA, micronuclei, or "speckles", ssDNA foci less aggregated than micronuclei), triggering the synthesis of cytokines and the activation of immune responses [19,20,80,337]. This non-cell-autonomous arm of the RSR is mainly mediated by the cyclic-GMP-AMP synthase-Stimulator of Interferon Genes (cGAS-STING) pathway.…”