Research carried out on the Institute of Molecular Biology and Biotechnology (IMBB) of FORTH, offers proof that persistent DNA injury triggers an exosome-based, metabolic reprogramming that results in continual irritation and tissue pathology in DNA repair-deficient progeroid syndromes and sure additionally throughout growing old.
Inborn defects in DNA restore mechanisms are related to most cancers and growing old but additionally with advanced metabolic and endocrine problems whose causal mechanisms will not be nicely understood. Using animals with a DNA restore, the IMBB researchers present a novel mechanism by which DNA injury results in mobile senescence, fibrosis, lack of tissue structure and chronic pancreatitis in mice. These findings led the workforce to suggest a brand new therapeutic technique, aimed toward combating chronic inflammation and tissue damage related to growing old. The findings pave the best way for novel rationalized intervention methods in opposition to age-related continual inflammatory problems.
Using ERCC1-defective animal fashions of the human progeroid syndrome XFE, the researchers revealed that the gradual accumulation of irreparable DNA lesions results in the untimely onset of continual pancreatitis within the DNA repair-deficient animals. Further work on cells from these animals revealed that DNA injury triggers the formation of RNA: DNA hybrids referred to as “R-loops” causally contributed to the discharge and build-up of single-stranded DNA fragments within the cytoplasm of cells. In flip, the cytoplasmic DNA fragments stimulated a viral-like immune response within the pancreas of DNA repair-defective and naturally aged mice. To scale back the proinflammatory load, the researchers developed an extracellular vesicle (EV)-based technique to ship recombinant RNase H or S1 nuclease in infected Ercc1-/- pancreatic cells in vitro and in vivo. Using this novel technique, they discovered that therapy with the EV-delivered nuclease cargo quickly removes R-loops and the ssDNA moieties within the cytoplasm of pancreatic cells, thereby lowering the proinflammatory response seen within the DNA restore poor mice.
The findings assist the notion that the event of EV-based therapeutic regimens in opposition to DNA damage-driven cytoplasmic ssDNAs is a promising therapeutic technique in opposition to continual irritation and tissue degeneration related to growing old.
Ourania Chatzidoukaki et al, R-loops set off the discharge of cytoplasmic ssDNAs resulting in continual irritation upon DNA injury, Science Advances (2021). DOI: 10.1126/sciadv.abj5769
Foundation for Research and Technology – Hellas
DNA injury in tissue-infiltrating macrophages triggers an exosome-based metabolic reprogram (2021, November 26)
retrieved 26 November 2021
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