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dc.contributor.author
Günther, Claudia
dc.contributor.author
Kind, Barbara
dc.contributor.author
Reijns, Martin A.M.
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Berndt, Nicole
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Martinez-Bueno, Manuel
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Wolf, Christine
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Tüngler, Victoria
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Chara, Osvaldo
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Lee, Young Ae
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Hübner, Norbert
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Bicknell, Louise
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Blum, Sophia
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Krug, Claudia
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Schmidt, Franziska
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Kretschmer, Stefanie
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Koss, Sarah
dc.contributor.author
Astell, Katy R.
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Ramantani, Georgia
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Bauerfeind, Anja
dc.contributor.author
Morris, David L.
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Graham, Deborah S. Cunninghame
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Bubeck, Doryen
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Leitch, Andrea
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Ralston, Stuart H.
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Blackburn, Elizabeth A.
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Gahr, Manfred
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Witte, Torsten
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Vyse, Timothy J.
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Melchers, Inga
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Mangold, Elisabeth
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Nöthen, Markus M.
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Aringer, Martin
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Kuhn, Annegret
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Lüthke, Kirsten
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Unger, Leonore
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Bley, Annette
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Lorenzi, Alice
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Isaacs, John D.
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Alexopoulou, Dimitra
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Conrad, Karsten
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Dahl, Andreas
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Roers, Axel
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Alarcon-Riquelme, Marta E.
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Jackson, Andrew P.
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Lee-Kirsch, Min Ae
dc.date.available
2021-02-12T12:48:35Z
dc.date.issued
2015-01
dc.identifier.citation
Günther, Claudia; Kind, Barbara; Reijns, Martin A.M.; Berndt, Nicole; Martinez-Bueno, Manuel; et al.; Defective removal of ribonucleotides from DNA promotes systemic autoimmunity; American Society for Clinical Investigation; Journal of Clinical Investigation; 125; 1; 1-2015; 413-424
dc.identifier.issn
0021-9738
dc.identifier.uri
http://hdl.handle.net/11336/125569
dc.description.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.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
American Society for Clinical Investigation
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Autoimmunity
dc.subject
Rnase H2
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Aicardi-Goutieres Syndrome
dc.subject
Lupus Erythematosus
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Otras Ciencias Médicas
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Otras Ciencias Médicas
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CIENCIAS MÉDICAS Y DE LA SALUD
dc.title
Defective removal of ribonucleotides from DNA promotes systemic autoimmunity
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2018-02-27T14:16:43Z
dc.identifier.eissn
1558-8238
dc.journal.volume
125
dc.journal.number
1
dc.journal.pagination
413-424
dc.journal.pais
Estados Unidos
dc.journal.ciudad
Ann Arbor, Michigan
dc.description.fil
Fil: Günther, Claudia. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
dc.description.fil
Fil: Kind, Barbara. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
dc.description.fil
Fil: Reijns, Martin A.M.. Medical Research Council Human Genetics Unit; Reino Unido
dc.description.fil
Fil: Berndt, Nicole. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
dc.description.fil
Fil: Martinez-Bueno, Manuel. Universidad de Granada; España
dc.description.fil
Fil: Wolf, Christine. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
dc.description.fil
Fil: Tüngler, Victoria. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
dc.description.fil
Fil: Chara, Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina
dc.description.fil
Fil: Lee, Young Ae. Max Delbruck Center For Molecular Medicine; Alemania
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Fil: Hübner, Norbert. Max Delbruck Center For Molecular Medicine; Alemania
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Fil: Bicknell, Louise. Medical Research Council Human Genetics Unit; Reino Unido
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Fil: Blum, Sophia. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
dc.description.fil
Fil: Krug, Claudia. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
dc.description.fil
Fil: Schmidt, Franziska. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
dc.description.fil
Fil: Kretschmer, Stefanie. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
dc.description.fil
Fil: Koss, Sarah. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
dc.description.fil
Fil: Astell, Katy R.. Medical Research Council Human Genetics Unit; Reino Unido
dc.description.fil
Fil: Ramantani, Georgia. Universität Freiburg Im Breisgau; Alemania
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Fil: Bauerfeind, Anja. Max Delbruck Center For Molecular Medicine; Alemania
dc.description.fil
Fil: Morris, David L.. King's College London; Reino Unido
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Fil: Graham, Deborah S. Cunninghame. King's College London; Reino Unido
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Fil: Bubeck, Doryen. Imperial College London; Reino Unido
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Fil: Leitch, Andrea. Edinburgh Medical School, Medical Research Council Human Genetics Unit; Alemania
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Fil: Ralston, Stuart H.. University of Edinburgh; Reino Unido
dc.description.fil
Fil: Blackburn, Elizabeth A.. University of Edinburgh; Reino Unido
dc.description.fil
Fil: Gahr, Manfred. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
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Fil: Witte, Torsten. Medizinische Hochschule Hannover; Alemania
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Fil: Vyse, Timothy J.. King's College London; Reino Unido
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Fil: Melchers, Inga. Universitäts Klinikum Freiburg Und Medizinische Fakultät; Alemania
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Fil: Mangold, Elisabeth. Universitäts-klinikum Bonn Und Medizinische Fakultät; Alemania
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Fil: Nöthen, Markus M.. Universitat Bonn; Alemania
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Fil: Aringer, Martin. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
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Fil: Kuhn, Annegret. Universitätsklinikum Münster; Alemania
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Fil: Lüthke, Kirsten. Schwerpunktpraxis Rheumatologie; Alemania
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Fil: Unger, Leonore. Krankenhaus Dresden-friedrichstadt; Alemania
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Fil: Bley, Annette. Universitat Hamburg; Alemania
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Fil: Lorenzi, Alice. University of Newcastle; Reino Unido
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Fil: Isaacs, John D.. University of Newcastle; Reino Unido
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Fil: Alexopoulou, Dimitra. Center For Regenerative Therapies Dresden; Alemania
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Fil: Conrad, Karsten. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
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Fil: Dahl, Andreas. Center For Regenerative Therapies Dresden; Alemania
dc.description.fil
Fil: Roers, Axel. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
dc.description.fil
Fil: Alarcon-Riquelme, Marta E.. Universidad de Granada; España. Oklahoma Medical Research Foundation; Estados Unidos
dc.description.fil
Fil: Jackson, Andrew P.. Medical Research Council Human Genetics Unit; Reino Unido
dc.description.fil
Fil: Lee-Kirsch, Min Ae. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
dc.journal.title
Journal of Clinical Investigation
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.jci.org/articles/view/78001
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1172/JCI78001
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