R-loops Trigger the Release of Cytoplasmic SsDNAs Leading to Chronic Inflammation Upon DNA Damage

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2021 Nov 19

PMID 34797720

Citations 24

Authors

Ourania Chatzidoukaki

Kalliopi Stratigi

Evi Goulielmaki

George Niotis

Alexia Akalestou-Clocher

Katerina Gkirtzimanaki

Alexandros Zafeiropoulos

Janine Altmuller

Pantelis Topalis

George A Garinis

Affiliations

Soon will be listed here.

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 () 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 pancreatic cells. Treatment of 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, paving the way for novel rationalized intervention strategies against age-related chronic inflammation.

Citing Articles

Thirty Years of BRCA1: Mechanistic Insights and Their Impact on Mutation Carriers.

Moser S, Jonkers J Cancer Discov. 2025; 15(3):461-480.

PMID: 40025950 PMC: 11893084. DOI: 10.1158/2159-8290.CD-24-1326.

Multi-modal investigation reveals pathogenic features of diverse DDX3X missense mutations.

Mosti F, Hoye M, Escobar-Tomlienovich C, Silver D PLoS Genet. 2025; 21(1):e1011555.

PMID: 39836689 PMC: 11771946. DOI: 10.1371/journal.pgen.1011555.

NUFIP1 integrates amino acid sensing and DNA damage response to maintain the intestinal homeostasis.

Ming H, Tan J, Cao S, Yu C, Qi Y, Wang C Nat Metab. 2025; 7(1):120-136.

PMID: 39753713 DOI: 10.1038/s42255-024-01179-5.

The Smc5/6 complex counteracts R-loop formation at highly transcribed genes in cooperation with RNase H2.

Roy S, Adhikary H, Isler S, DAmours D Elife. 2024; 13.

PMID: 39404251 PMC: 11620742. DOI: 10.7554/eLife.96626.

R-loops and impaired autophagy trigger cGAS-dependent inflammation via micronuclei formation in Senataxin-deficient cells.

Zannini L, Cardano M, Liberi G, Buscemi G Cell Mol Life Sci. 2024; 81(1):339.

PMID: 39120648 PMC: 11335261. DOI: 10.1007/s00018-024-05380-3.

References

Rieckher M, Garinis G, Schumacher B . Molecular pathology of rare progeroid diseases. Trends Mol Med. 2021; 27(9):907-922. DOI: 10.1016/j.molmed.2021.06.011. View

Chatzinikolaou G, Karakasilioti I, Garinis G . DNA damage and innate immunity: links and trade-offs. Trends Immunol. 2014; 35(9):429-35. DOI: 10.1016/j.it.2014.06.003. View

Huertas P, Aguilera A . Cotranscriptionally formed DNA:RNA hybrids mediate transcription elongation impairment and transcription-associated recombination. Mol Cell. 2003; 12(3):711-21. DOI: 10.1016/j.molcel.2003.08.010. View

Tuduri S, Crabbe L, Conti C, Tourriere H, Holtgreve-Grez H, Jauch A . Topoisomerase I suppresses genomic instability by preventing interference between replication and transcription. Nat Cell Biol. 2009; 11(11):1315-24. PMC: 2912930. DOI: 10.1038/ncb1984. View

Wold M . Replication protein A: a heterotrimeric, single-stranded DNA-binding protein required for eukaryotic DNA metabolism. Annu Rev Biochem. 1997; 66:61-92. DOI: 10.1146/annurev.biochem.66.1.61. View

Farkash E, Luning Prak E . DNA damage and L1 retrotransposition. J Biomed Biotechnol. 2006; 2006(1):37285. PMC: 1559917. DOI: 10.1155/JBB/2006/37285. View

Chatzidoukaki O, Goulielmaki E, Schumacher B, Garinis G . DNA Damage Response and Metabolic Reprogramming in Health and Disease. Trends Genet. 2020; 36(10):777-791. DOI: 10.1016/j.tig.2020.06.018. View

Stratigi K, Chatzidoukaki O, Garinis G . DNA damage-induced inflammation and nuclear architecture. Mech Ageing Dev. 2016; 165(Pt A):17-26. DOI: 10.1016/j.mad.2016.09.008. View

Sato K, Ishiai M, Toda K, Furukoshi S, Osakabe A, Tachiwana H . Histone chaperone activity of Fanconi anemia proteins, FANCD2 and FANCI, is required for DNA crosslink repair. EMBO J. 2012; 31(17):3524-36. PMC: 3433790. DOI: 10.1038/emboj.2012.197. View

10.

Mackenzie K, Carroll P, Lettice L, Tarnauskaite Z, Reddy K, Dix F . Ribonuclease H2 mutations induce a cGAS/STING-dependent innate immune response. EMBO J. 2016; 35(8):831-44. PMC: 4855687. DOI: 10.15252/embj.201593339. View

11.

Goulielmaki E, Ioannidou A, Tsekrekou M, Stratigi K, Poutakidou I, Gkirtzimanaki K . Tissue-infiltrating macrophages mediate an exosome-based metabolic reprogramming upon DNA damage. Nat Commun. 2020; 11(1):42. PMC: 6940362. DOI: 10.1038/s41467-019-13894-9. View

12.

Ginno P, Lott P, Christensen H, Korf I, Chedin F . R-loop formation is a distinctive characteristic of unmethylated human CpG island promoters. Mol Cell. 2012; 45(6):814-25. PMC: 3319272. DOI: 10.1016/j.molcel.2012.01.017. View

13.

Hanawalt P . Subpathways of nucleotide excision repair and their regulation. Oncogene. 2002; 21(58):8949-56. DOI: 10.1038/sj.onc.1206096. View

14.

Shen W, Sun H, De Hoyos C, Bailey J, Liang X, Crooke S . Dynamic nucleoplasmic and nucleolar localization of mammalian RNase H1 in response to RNAP I transcriptional R-loops. Nucleic Acids Res. 2017; 45(18):10672-10692. PMC: 5737507. DOI: 10.1093/nar/gkx710. View

15.

Lohr J, Panic N, Vujasinovic M, Verbeke C . The ageing pancreas: a systematic review of the evidence and analysis of the consequences. J Intern Med. 2018; 283(5):446-460. DOI: 10.1111/joim.12745. View

16.

Baltimore D . Discovering NF-kappaB. Cold Spring Harb Perspect Biol. 2010; 1(1):a000026. PMC: 2742082. DOI: 10.1101/cshperspect.a000026. View

17.

van der Pluijm I, Garinis G, Brandt R, Gorgels T, Wijnhoven S, Diderich K . Impaired genome maintenance suppresses the growth hormone--insulin-like growth factor 1 axis in mice with Cockayne syndrome. PLoS Biol. 2007; 5(1):e2. PMC: 1698505. DOI: 10.1371/journal.pbio.0050002. View

18.

Huerta Guevara A, McGowan S, Kazantzis M, Stallons T, Sano T, Mulder N . Increased insulin sensitivity and diminished pancreatic beta-cell function in DNA repair deficient Ercc1 mice. Metabolism. 2021; 117:154711. PMC: 8625516. DOI: 10.1016/j.metabol.2021.154711. View

19.

Takai H, Smogorzewska A, de Lange T . DNA damage foci at dysfunctional telomeres. Curr Biol. 2003; 13(17):1549-56. DOI: 10.1016/s0960-9822(03)00542-6. View

20.

Marteijn J, Lans H, Vermeulen W, Hoeijmakers J . Understanding nucleotide excision repair and its roles in cancer and ageing. Nat Rev Mol Cell Biol. 2014; 15(7):465-81. DOI: 10.1038/nrm3822. View