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Lookup NU author(s): Dr Alice Lorenzi,
Professor John IsaacsORCiD
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Genome integrity is continuously challenged by the DNA damage that arises during normal cell metabolism. Biallelic mutations in the genes encoding the genome surveillance enzyme ribonuclease H2 (RNase H2) cause Aicardi-Goutieres syndrome (AGS), a pediatric disorder that shares features with the autoimmune disease systemic lupus erythematosus (SLE). Here we determined that heterozygous parents of AGS patients exhibit an intermediate autoimmune phenotype and demonstrated a genetic association between rare RNASEH2 sequence variants and SLE. Evaluation of patient cells revealed that SLE- and AGS-associated mutations impair RNase H2 function and result in accumulation of ribonucleotides in genomic DNA. The ensuing chronic low level of DNA damage triggered a DNA damage response characterized by constitutive p53 phosphorylation and senescence. Patient fibroblasts exhibited constitutive upregulation of IFN-stimulated genes and an enhanced type I IFN response to the immunostimulatory nucleic acid polyinosinic:polycytidylic acid and UV light irradiation, linking RNase H2 deficiency to potentiation of innate immune signaling. Moreover, UV-induced cyclobutane pyrimidine dimer formation was markedly enhanced in ribonucleotide-containing DNA, providing a mechanism for photosensitivity in RNase H2-associated SLE. Collectively, our findings implicate RNase H2 in the pathogenesis of SLE and suggest a role of DNA damage-associated pathways in the initiation of autoimmunity.
Author(s): Gunther C, Kind B, Reijns MAM, Berndt N, Martinez-Bueno M, Wolf C, Tungler V, Chara O, Lee YA, Hubner N, Bicknell L, Blum S, Krug C, Schmidt F, Kretschmer S, Koss S, Astell KR, Ramantani G, Bauerfeind A, Morris DL, Graham DSC, Bubeck D, Leitch A, Ralston SH, Blackburn EA, Gahr M, Witte T, Vyse TJ, Melchers I, Mangold E, Nothen MM, Aringer M, Kuhn A, Luthke K, Unger L, Bley A, Lorenzi A, Isaacs JD, Alexopoulou D, Conrad K, Dahl A, Roers A, Alarcon-Riquelme ME, Jackson AP, Lee-Kirsch MA
Publication type: Article
Publication status: Published
Journal: Journal of Clinical Investigation
Print publication date: 02/01/2015
Online publication date: 15/12/2014
Acceptance date: 09/10/2014
ISSN (print): 0021-9738
ISSN (electronic): 1558-8238
Publisher: American Society for Clinical Investigation
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