Universität zu Köln

Chatzidoukaki, Ourania ORCID: 0000-0002-8746-2405, Stratigi, Kalliopi, Goulielmaki, Evi, Niotis, George ORCID: 0000-0002-4874-7336, Akalestou-Clocher, Alexia, Gkirtzimanaki, Katerina ORCID: 0000-0002-6489-0351, Zafeiropoulos, Alexandros, Altmueller, Janine, Topalis, Pantelis ORCID: 0000-0002-1635-4810 and Garinis, George A. (2021). R-loops trigger the release of cytoplasmic ssDNAs leading to chronic inflammation upon DNA damage. Sci. Adv., 7 (47). WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 2375-2548

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Chatzidoukaki, Ourania UNSPECIFIED orcid.org/0000-0002-8746-2405 UNSPECIFIED Stratigi, Kalliopi UNSPECIFIED UNSPECIFIED UNSPECIFIED Goulielmaki, Evi UNSPECIFIED UNSPECIFIED UNSPECIFIED Niotis, George UNSPECIFIED orcid.org/0000-0002-4874-7336 UNSPECIFIED Akalestou-Clocher, Alexia UNSPECIFIED UNSPECIFIED UNSPECIFIED Gkirtzimanaki, Katerina UNSPECIFIED orcid.org/0000-0002-6489-0351 UNSPECIFIED Zafeiropoulos, Alexandros UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Topalis, Pantelis UNSPECIFIED orcid.org/0000-0002-1635-4810 UNSPECIFIED Garinis, George A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-583112
DOI:	10.1126/sciadv.abj5769
Journal or Publication Title:	Sci. Adv.
Volume:	7
Number:	47
Date:	2021
Publisher:	AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication:	WASHINGTON
ISSN:	2375-2548
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NUCLEOTIDE EXCISION-REPAIR; REPLICATION; SENESCENCE; HYBRIDS; SUPPRESSES; ERCC1-XPF; MEDIATOR; REVEALS; INDUCE; ERCC4 Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/58311