R-loops trigger the release of cytoplasmic ssDNAs leading to chronic inflammation upon DNA damage.
Sci Adv
; 7(47): eabj5769, 2021 11 19.
Article
in En
| MEDLINE
| ID: mdl-34797720
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
DNA Repair
/
R-Loop Structures
Limits:
Animals
Language:
En
Journal:
Sci Adv
Year:
2021
Document type:
Article
Affiliation country:
Greece