R-loops trigger the release of cytoplasmic ssDNAs leading to chronic inflammation upon DNA damage


  • O. Chatzidoukaki
  • K. Stratigi
  • E. Goulielmaki
  • G. Niotis
  • A. Akalestou-Clocher
  • K. Gkirtzimanaki
  • A. Zafeiropoulos
  • J. Altmüller
  • P. Topalis
  • G.A. Garinis


  • Science Advances


  • Sci Adv 7 (47): eabj5769


  • How DNA damage leads to chronic inflammation and tissue degeneration with aging remains to be fully resolved. Here, we show that DNA damage leads to cellular senescence, fibrosis, loss-of-tissue architecture, and chronic pancreatitis in mice with an inborn defect in the excision repair cross complementation group 1 (Ercc1) gene. We find that DNA damage-driven R-loops causally contribute to the active release and buildup of single-stranded DNAs (ssDNAs) in the cytoplasm of cells triggering a viral-like immune response in progeroid and naturally aged pancreata. To reduce the proinflammatory load, we developed an extracellular vesicle (EV)-based strategy to deliver recombinant S1 or ribonuclease H nucleases in inflamed Ercc1(−/−) pancreatic cells. Treatment of Ercc1(−/−) animals with the EV-delivered nuclease cargo eliminates DNA damage-induced R-loops and cytoplasmic ssDNAs alleviating chronic inflammation. Thus, DNA damage-driven ssDNAs causally contribute to tissue degeneration, Ercc1(−/−) paving the way for novel rationalized intervention strategies against age-related chronic inflammation.