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

Ourania Chatzidoukaki1,2, Kalliopi Stratigi1, Evi Goulielmaki1

  • 1Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, GR70013 Heraklion, Crete, Greece.

Science Advances
|November 19, 2021
PubMed

Insights

DNA damage causes chronic inflammation and tissue aging. Extracellular vesicles delivering nucleases cleared DNA damage, reducing inflammation and suggesting new therapies for age-related diseases.

Area of Science:

  • Molecular Biology
  • Immunology
  • Geroscience

Background:

  • DNA damage accumulation is linked to aging and chronic inflammation.
  • The precise mechanisms connecting DNA damage to tissue degeneration are not fully understood.

Purpose of the Study:

  • To investigate the role of DNA damage in chronic pancreatitis and tissue degeneration.
  • To explore therapeutic strategies for mitigating DNA damage-induced inflammation.

Main Methods:

  • Utilized Ercc1-deficient mice exhibiting DNA damage.
  • Investigated DNA damage-induced R-loops and cytoplasmic ssDNAs.
  • Developed an extracellular vesicle (EV)-based delivery system for nucleases.

Main Results:

  • DNA damage in Ercc1-deficient mice led to cellular senescence, fibrosis, and chronic pancreatitis.
  • DNA damage-driven R-loops caused cytoplasmic ssDNA buildup, triggering an immune response.
  • EV-delivered nucleases successfully eliminated R-loops and cytoplasmic ssDNAs, reducing inflammation.

Conclusions:

  • DNA damage-induced ssDNAs are a causal factor in age-related tissue degeneration and chronic inflammation.
  • EV-mediated nuclease delivery offers a promising therapeutic approach for age-related inflammatory conditions.

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