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Defective removal of ribonucleotides from DNA promotes systemic autoimmunity

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Official URL:https://doi.org/10.1172/JCI78001
PubMed:View item in PubMed
Creators Name:Guenther, C. and Kind, B. and Reijns, M.A.M. and Berndt, N. and Martinez-Bueno, M. and Wolf, C. and Tuengler, V. and Chara, O. and Lee, Y.A. and Huebner, N. and Bicknell, L. and Blum, S. and Krug, C. and Schmidt, F. and Kretschmer, S. and Koss, S. and Astell, K.R. and Ramantani, G. and Bauerfeind, A. and Morris, D.L. and Cunninghame Graham, D.S. and Bubeck, D. and Leitch, A. and Ralston, S.H. and Blackburn, E.A. and Gahr, M. and Witte, T. and Vyse, T.J. and Melchers, I. and Mangold, E. and Noethen, M.M. and Aringer, M. and Kuhn, A. and Luethke, K. and Unger, L. and Bley, A. and Lorenzi, A. and Isaacs, J.D. and Alexopoulou, D. and Conrad, K. and Dahl, A. and Roers, A. and Alarcon-Riquelme, M.E. and Jackson, A.P. and Lee-Kirsch, M.A.
Journal Title:Journal of Clinical Investigation
Journal Abbreviation:J Clin Invest
Volume:125
Number:1
Page Range:413-424
Date:2 January 2015
Keywords:Autoimmunity, Cell Proliferation, Cultured Cells, DNA Mutational Analysis, DNA Repair, Gene Expression, Heterozygote, Interferon Type I, Pyrimidine Dimers, Ribonuclease H, Systemic Lupus Erythematosus
Abstract: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-Goutières 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.
ISSN:0021-9738
Publisher:American Society for Clinical Investigation (U.S.A.)
Item Type:Article

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