DNA Damage Triggers Cytoplasmic SsDNA Accumulation Leading to Chronic Inflammation in NER Progeria

To alert the immune system to the danger posed by DNA damage itself, cells often trigger “nuclear-to-cytoplasmic” signals associated with the activation of nuclear factors, cell surface ligands and the release of pro-inflammatory cytokines. At present, however, it remains unclear how DNA damage is functionally linked to innate immune signaling, what are the underlying mediators or how such responses impinge on cell viability and organismal survival over time. To tackle this, we utilize a comprehensive and multidisciplinary approach to dissect the causal contribution of irreparable DNA lesions and the DNA damage response to chronic inflammation during (accelerated) ageing. Using a NER progeroid animal model, we find that persistent DNA damage triggers the transcription-dependent generation and subsequent nucleo-cytoplasmic transport of ssDNA moieties. Further work reveals that the rapid accumulation of cytosolic ssDNAs enables DNA sensors to activate innate immune signaling pathways, leading to the induction of pro-inflammatory responses. Our research strategy provides us with insights onto how nuclear DNA damage sensors liaise with innate immune signaling in the cytoplasm and how both processes impinge on cell homeostasis and age-related chronic inflammation.