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Defective removal of ribonucleotides from DNA promotes systemic autoimmunity
Claudia Günther, … , Andrew P. Jackson, Min Ae Lee-Kirsch
Claudia Günther, … , Andrew P. Jackson, Min Ae Lee-Kirsch
Published December 15, 2014
Citation Information: J Clin Invest. 2015;125(1):413-424. https://doi.org/10.1172/JCI78001.
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Research Article Article has an altmetric score of 18

Defective removal of ribonucleotides from DNA promotes systemic autoimmunity

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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.

Authors

Claudia Günther, Barbara Kind, Martin A.M. Reijns, Nicole Berndt, Manuel Martinez-Bueno, Christine Wolf, Victoria Tüngler, Osvaldo Chara, Young Ae Lee, Norbert Hübner, Louise Bicknell, Sophia Blum, Claudia Krug, Franziska Schmidt, Stefanie Kretschmer, Sarah Koss, Katy R. Astell, Georgia Ramantani, Anja Bauerfeind, David L. Morris, Deborah S. Cunninghame Graham, Doryen Bubeck, Andrea Leitch, Stuart H. Ralston, Elizabeth A. Blackburn, Manfred Gahr, Torsten Witte, Timothy J. Vyse, Inga Melchers, Elisabeth Mangold, Markus M. Nöthen, Martin Aringer, Annegret Kuhn, Kirsten Lüthke, Leonore Unger, Annette Bley, Alice Lorenzi, John D. Isaacs, Dimitra Alexopoulou, Karsten Conrad, Andreas Dahl, Axel Roers, Marta E. Alarcon-Riquelme, Andrew P. Jackson, Min Ae Lee-Kirsch

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Figure 6

Increased sensitivity to photodamage in ribonucleotide-containing DNA.

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Increased sensitivity to photodamage in ribonucleotide-containing DNA.
(...
(A) Increased CPD formation in RNase H2–deficient fibroblasts (SLE1, SLE2, AGS1, and AGS2) compared with WT in response to 20 J/m2 UVC, measured immediately or 7 and 24 hours after irradiation. Box plots depict interquartile range (box), mean (square), median (line) and SD (whisker) of ≥3 independent experiments per patient and for 5 WT cell lines. *P < 0.05, **P < 0.01, ***P < 0.001 versus WT, t test. (B and C) Dihedral angles between covalent C5-C6 bonds (B) and pyrimidine ring planes (C) of 2 consecutive thymidines of the unmodified (1NAJ) and the ribonucleotide-containing (2L7D) Dickerson dodecamer. Ribonucleotide substitution increased colinearity between C5-C6 covalent bonds and coplanarity between pyrimidine rings, enhancing the probability of a photoreactive dimerization. For each dodecamer, 5 structures deposited in PDB were compared. Mean and SD shown. ***P < 0.001 versus 1NAJ, t test. (D) CPD formation in genomic DNA from fibroblasts of individual RNase H2–deficient versus WT patients and from Rnaseh2b–/– versus WT MEFs (n = 2 per group). Representative dot blot and mean intensities with SEM of 3 independent experiments are shown. *P < 0.05, **P < 0.01, ***P < 0.001 versus WT, t test. (E) CPD formation in double-stranded concatamers of chimeric DNA oligonucleotides containing 3 Dickerson dodecamer sequences in tandem. Replacement of a deoxyriboguanosine at position 4 of the dodecamer by a riboguanosine (R) is indicated.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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