Defective removal of ribonucleotides from DNA promotes systemic autoimmunity

Autores
Günther, Claudia; Kind, Barbara; Reijns, Martin A.M.; Berndt, Nicole; Martinez-Bueno, Manuel; Wolf, Christine; Tüngler, Victoria; Chara, Osvaldo; Lee, Young Ae; Hübner, Norbert; Bicknell, Louise; Blum, Sophia; Krug, Claudia; Schmidt, Franziska; Kretschmer, Stefanie; Koss, Sarah; Astell, Katy R.; Ramantani, Georgia; Bauerfeind, Anja; Morris, David L.; Graham, Deborah S. Cunninghame; Bubeck, Doryen; Leitch, Andrea; Ralston, Stuart H.; Blackburn, Elizabeth A.; Gahr, Manfred; Witte, Torsten; Vyse, Timothy J.; Melchers, Inga; Mangold, Elisabeth; Nöthen, Markus M.; Aringer, Martin; Kuhn, Annegret; Lüthke, Kirsten; Unger, Leonore; Bley, Annette; Lorenzi, Alice; Isaacs, John D.; Alexopoulou, Dimitra; Conrad, Karsten; Dahl, Andreas; Roers, Axel; Alarcon-Riquelme, Marta E.; Jackson, Andrew P.; Lee-Kirsch, Min Ae
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Günther, Claudia. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Kind, Barbara. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Reijns, Martin A.M.. Medical Research Council Human Genetics Unit; Reino Unido
Fil: Berndt, Nicole. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Martinez-Bueno, Manuel. Universidad de Granada; España
Fil: Wolf, Christine. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Tüngler, Victoria. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
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
Fil: Lee, Young Ae. Max Delbruck Center For Molecular Medicine; Alemania
Fil: Hübner, Norbert. Max Delbruck Center For Molecular Medicine; Alemania
Fil: Bicknell, Louise. Medical Research Council Human Genetics Unit; Reino Unido
Fil: Blum, Sophia. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Krug, Claudia. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Schmidt, Franziska. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Kretschmer, Stefanie. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Koss, Sarah. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Astell, Katy R.. Medical Research Council Human Genetics Unit; Reino Unido
Fil: Ramantani, Georgia. Universität Freiburg Im Breisgau; Alemania
Fil: Bauerfeind, Anja. Max Delbruck Center For Molecular Medicine; Alemania
Fil: Morris, David L.. King's College London; Reino Unido
Fil: Graham, Deborah S. Cunninghame. King's College London; Reino Unido
Fil: Bubeck, Doryen. Imperial College London; Reino Unido
Fil: Leitch, Andrea. Edinburgh Medical School, Medical Research Council Human Genetics Unit; Alemania
Fil: Ralston, Stuart H.. University of Edinburgh; Reino Unido
Fil: Blackburn, Elizabeth A.. University of Edinburgh; Reino Unido
Fil: Gahr, Manfred. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Witte, Torsten. Medizinische Hochschule Hannover; Alemania
Fil: Vyse, Timothy J.. King's College London; Reino Unido
Fil: Melchers, Inga. Universitäts Klinikum Freiburg Und Medizinische Fakultät; Alemania
Fil: Mangold, Elisabeth. Universitäts-klinikum Bonn Und Medizinische Fakultät; Alemania
Fil: Nöthen, Markus M.. Universitat Bonn; Alemania
Fil: Aringer, Martin. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Kuhn, Annegret. Universitätsklinikum Münster; Alemania
Fil: Lüthke, Kirsten. Schwerpunktpraxis Rheumatologie; Alemania
Fil: Unger, Leonore. Krankenhaus Dresden-friedrichstadt; Alemania
Fil: Bley, Annette. Universitat Hamburg; Alemania
Fil: Lorenzi, Alice. University of Newcastle; Reino Unido
Fil: Isaacs, John D.. University of Newcastle; Reino Unido
Fil: Alexopoulou, Dimitra. Center For Regenerative Therapies Dresden; Alemania
Fil: Conrad, Karsten. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Dahl, Andreas. Center For Regenerative Therapies Dresden; Alemania
Fil: Roers, Axel. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Alarcon-Riquelme, Marta E.. Universidad de Granada; España. Oklahoma Medical Research Foundation; Estados Unidos
Fil: Jackson, Andrew P.. Medical Research Council Human Genetics Unit; Reino Unido
Fil: Lee-Kirsch, Min Ae. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Materia
Autoimmunity
Rnase H2
Aicardi-Goutieres Syndrome
Lupus Erythematosus
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/125569

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oai_identifier_str oai:ri.conicet.gov.ar:11336/125569
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Defective removal of ribonucleotides from DNA promotes systemic autoimmunityGünther, ClaudiaKind, BarbaraReijns, Martin A.M.Berndt, NicoleMartinez-Bueno, ManuelWolf, ChristineTüngler, VictoriaChara, OsvaldoLee, Young AeHübner, NorbertBicknell, LouiseBlum, SophiaKrug, ClaudiaSchmidt, FranziskaKretschmer, StefanieKoss, SarahAstell, Katy R.Ramantani, GeorgiaBauerfeind, AnjaMorris, David L.Graham, Deborah S. CunninghameBubeck, DoryenLeitch, AndreaRalston, Stuart H.Blackburn, Elizabeth A.Gahr, ManfredWitte, TorstenVyse, Timothy J.Melchers, IngaMangold, ElisabethNöthen, Markus M.Aringer, MartinKuhn, AnnegretLüthke, KirstenUnger, LeonoreBley, AnnetteLorenzi, AliceIsaacs, John D.Alexopoulou, DimitraConrad, KarstenDahl, AndreasRoers, AxelAlarcon-Riquelme, Marta E.Jackson, Andrew P.Lee-Kirsch, Min AeAutoimmunityRnase H2Aicardi-Goutieres SyndromeLupus Erythematosushttps://purl.org/becyt/ford/3.5https://purl.org/becyt/ford/3Genome 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.Fil: Günther, Claudia. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; AlemaniaFil: Kind, Barbara. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; AlemaniaFil: Reijns, Martin A.M.. Medical Research Council Human Genetics Unit; Reino UnidoFil: Berndt, Nicole. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; AlemaniaFil: Martinez-Bueno, Manuel. Universidad de Granada; EspañaFil: Wolf, Christine. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; AlemaniaFil: Tüngler, Victoria. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; AlemaniaFil: 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; ArgentinaFil: Lee, Young Ae. Max Delbruck Center For Molecular Medicine; AlemaniaFil: Hübner, Norbert. Max Delbruck Center For Molecular Medicine; AlemaniaFil: Bicknell, Louise. Medical Research Council Human Genetics Unit; Reino UnidoFil: Blum, Sophia. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; AlemaniaFil: Krug, Claudia. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; AlemaniaFil: Schmidt, Franziska. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; AlemaniaFil: Kretschmer, Stefanie. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; AlemaniaFil: Koss, Sarah. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; AlemaniaFil: Astell, Katy R.. Medical Research Council Human Genetics Unit; Reino UnidoFil: Ramantani, Georgia. Universität Freiburg Im Breisgau; AlemaniaFil: Bauerfeind, Anja. Max Delbruck Center For Molecular Medicine; AlemaniaFil: Morris, David L.. King's College London; Reino UnidoFil: Graham, Deborah S. Cunninghame. King's College London; Reino UnidoFil: Bubeck, Doryen. Imperial College London; Reino UnidoFil: Leitch, Andrea. Edinburgh Medical School, Medical Research Council Human Genetics Unit; AlemaniaFil: Ralston, Stuart H.. University of Edinburgh; Reino UnidoFil: Blackburn, Elizabeth A.. University of Edinburgh; Reino UnidoFil: Gahr, Manfred. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; AlemaniaFil: Witte, Torsten. Medizinische Hochschule Hannover; AlemaniaFil: Vyse, Timothy J.. King's College London; Reino UnidoFil: Melchers, Inga. Universitäts Klinikum Freiburg Und Medizinische Fakultät; AlemaniaFil: Mangold, Elisabeth. Universitäts-klinikum Bonn Und Medizinische Fakultät; AlemaniaFil: Nöthen, Markus M.. Universitat Bonn; AlemaniaFil: Aringer, Martin. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; AlemaniaFil: Kuhn, Annegret. Universitätsklinikum Münster; AlemaniaFil: Lüthke, Kirsten. Schwerpunktpraxis Rheumatologie; AlemaniaFil: Unger, Leonore. Krankenhaus Dresden-friedrichstadt; AlemaniaFil: Bley, Annette. Universitat Hamburg; AlemaniaFil: Lorenzi, Alice. University of Newcastle; Reino UnidoFil: Isaacs, John D.. University of Newcastle; Reino UnidoFil: Alexopoulou, Dimitra. Center For Regenerative Therapies Dresden; AlemaniaFil: Conrad, Karsten. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; AlemaniaFil: Dahl, Andreas. Center For Regenerative Therapies Dresden; AlemaniaFil: Roers, Axel. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; AlemaniaFil: Alarcon-Riquelme, Marta E.. Universidad de Granada; España. Oklahoma Medical Research Foundation; Estados UnidosFil: Jackson, Andrew P.. Medical Research Council Human Genetics Unit; Reino UnidoFil: Lee-Kirsch, Min Ae. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; AlemaniaAmerican Society for Clinical Investigation2015-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/125569Günther, 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; 413-4240021-97381558-8238CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.jci.org/articles/view/78001info:eu-repo/semantics/altIdentifier/doi/10.1172/JCI78001info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:11:59Zoai:ri.conicet.gov.ar:11336/125569instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:11:59.399CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Defective removal of ribonucleotides from DNA promotes systemic autoimmunity
title Defective removal of ribonucleotides from DNA promotes systemic autoimmunity
spellingShingle Defective removal of ribonucleotides from DNA promotes systemic autoimmunity
Günther, Claudia
Autoimmunity
Rnase H2
Aicardi-Goutieres Syndrome
Lupus Erythematosus
title_short Defective removal of ribonucleotides from DNA promotes systemic autoimmunity
title_full Defective removal of ribonucleotides from DNA promotes systemic autoimmunity
title_fullStr Defective removal of ribonucleotides from DNA promotes systemic autoimmunity
title_full_unstemmed Defective removal of ribonucleotides from DNA promotes systemic autoimmunity
title_sort Defective removal of ribonucleotides from DNA promotes systemic autoimmunity
dc.creator.none.fl_str_mv Günther, Claudia
Kind, Barbara
Reijns, Martin A.M.
Berndt, Nicole
Martinez-Bueno, Manuel
Wolf, Christine
Tüngler, Victoria
Chara, Osvaldo
Lee, Young Ae
Hübner, Norbert
Bicknell, Louise
Blum, Sophia
Krug, Claudia
Schmidt, Franziska
Kretschmer, Stefanie
Koss, Sarah
Astell, Katy R.
Ramantani, Georgia
Bauerfeind, Anja
Morris, David L.
Graham, Deborah S. Cunninghame
Bubeck, Doryen
Leitch, Andrea
Ralston, Stuart H.
Blackburn, Elizabeth A.
Gahr, Manfred
Witte, Torsten
Vyse, Timothy J.
Melchers, Inga
Mangold, Elisabeth
Nöthen, Markus M.
Aringer, Martin
Kuhn, Annegret
Lüthke, Kirsten
Unger, Leonore
Bley, Annette
Lorenzi, Alice
Isaacs, John D.
Alexopoulou, Dimitra
Conrad, Karsten
Dahl, Andreas
Roers, Axel
Alarcon-Riquelme, Marta E.
Jackson, Andrew P.
Lee-Kirsch, Min Ae
author Günther, Claudia
author_facet Günther, Claudia
Kind, Barbara
Reijns, Martin A.M.
Berndt, Nicole
Martinez-Bueno, Manuel
Wolf, Christine
Tüngler, Victoria
Chara, Osvaldo
Lee, Young Ae
Hübner, Norbert
Bicknell, Louise
Blum, Sophia
Krug, Claudia
Schmidt, Franziska
Kretschmer, Stefanie
Koss, Sarah
Astell, Katy R.
Ramantani, Georgia
Bauerfeind, Anja
Morris, David L.
Graham, Deborah S. Cunninghame
Bubeck, Doryen
Leitch, Andrea
Ralston, Stuart H.
Blackburn, Elizabeth A.
Gahr, Manfred
Witte, Torsten
Vyse, Timothy J.
Melchers, Inga
Mangold, Elisabeth
Nöthen, Markus M.
Aringer, Martin
Kuhn, Annegret
Lüthke, Kirsten
Unger, Leonore
Bley, Annette
Lorenzi, Alice
Isaacs, John D.
Alexopoulou, Dimitra
Conrad, Karsten
Dahl, Andreas
Roers, Axel
Alarcon-Riquelme, Marta E.
Jackson, Andrew P.
Lee-Kirsch, Min Ae
author_role author
author2 Kind, Barbara
Reijns, Martin A.M.
Berndt, Nicole
Martinez-Bueno, Manuel
Wolf, Christine
Tüngler, Victoria
Chara, Osvaldo
Lee, Young Ae
Hübner, Norbert
Bicknell, Louise
Blum, Sophia
Krug, Claudia
Schmidt, Franziska
Kretschmer, Stefanie
Koss, Sarah
Astell, Katy R.
Ramantani, Georgia
Bauerfeind, Anja
Morris, David L.
Graham, Deborah S. Cunninghame
Bubeck, Doryen
Leitch, Andrea
Ralston, Stuart H.
Blackburn, Elizabeth A.
Gahr, Manfred
Witte, Torsten
Vyse, Timothy J.
Melchers, Inga
Mangold, Elisabeth
Nöthen, Markus M.
Aringer, Martin
Kuhn, Annegret
Lüthke, Kirsten
Unger, Leonore
Bley, Annette
Lorenzi, Alice
Isaacs, John D.
Alexopoulou, Dimitra
Conrad, Karsten
Dahl, Andreas
Roers, Axel
Alarcon-Riquelme, Marta E.
Jackson, Andrew P.
Lee-Kirsch, Min Ae
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Autoimmunity
Rnase H2
Aicardi-Goutieres Syndrome
Lupus Erythematosus
topic Autoimmunity
Rnase H2
Aicardi-Goutieres Syndrome
Lupus Erythematosus
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.5
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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.
Fil: Günther, Claudia. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Kind, Barbara. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Reijns, Martin A.M.. Medical Research Council Human Genetics Unit; Reino Unido
Fil: Berndt, Nicole. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Martinez-Bueno, Manuel. Universidad de Granada; España
Fil: Wolf, Christine. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Tüngler, Victoria. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
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
Fil: Lee, Young Ae. Max Delbruck Center For Molecular Medicine; Alemania
Fil: Hübner, Norbert. Max Delbruck Center For Molecular Medicine; Alemania
Fil: Bicknell, Louise. Medical Research Council Human Genetics Unit; Reino Unido
Fil: Blum, Sophia. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Krug, Claudia. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Schmidt, Franziska. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Kretschmer, Stefanie. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Koss, Sarah. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Astell, Katy R.. Medical Research Council Human Genetics Unit; Reino Unido
Fil: Ramantani, Georgia. Universität Freiburg Im Breisgau; Alemania
Fil: Bauerfeind, Anja. Max Delbruck Center For Molecular Medicine; Alemania
Fil: Morris, David L.. King's College London; Reino Unido
Fil: Graham, Deborah S. Cunninghame. King's College London; Reino Unido
Fil: Bubeck, Doryen. Imperial College London; Reino Unido
Fil: Leitch, Andrea. Edinburgh Medical School, Medical Research Council Human Genetics Unit; Alemania
Fil: Ralston, Stuart H.. University of Edinburgh; Reino Unido
Fil: Blackburn, Elizabeth A.. University of Edinburgh; Reino Unido
Fil: Gahr, Manfred. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Witte, Torsten. Medizinische Hochschule Hannover; Alemania
Fil: Vyse, Timothy J.. King's College London; Reino Unido
Fil: Melchers, Inga. Universitäts Klinikum Freiburg Und Medizinische Fakultät; Alemania
Fil: Mangold, Elisabeth. Universitäts-klinikum Bonn Und Medizinische Fakultät; Alemania
Fil: Nöthen, Markus M.. Universitat Bonn; Alemania
Fil: Aringer, Martin. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Kuhn, Annegret. Universitätsklinikum Münster; Alemania
Fil: Lüthke, Kirsten. Schwerpunktpraxis Rheumatologie; Alemania
Fil: Unger, Leonore. Krankenhaus Dresden-friedrichstadt; Alemania
Fil: Bley, Annette. Universitat Hamburg; Alemania
Fil: Lorenzi, Alice. University of Newcastle; Reino Unido
Fil: Isaacs, John D.. University of Newcastle; Reino Unido
Fil: Alexopoulou, Dimitra. Center For Regenerative Therapies Dresden; Alemania
Fil: Conrad, Karsten. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Dahl, Andreas. Center For Regenerative Therapies Dresden; Alemania
Fil: Roers, Axel. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
Fil: Alarcon-Riquelme, Marta E.. Universidad de Granada; España. Oklahoma Medical Research Foundation; Estados Unidos
Fil: Jackson, Andrew P.. Medical Research Council Human Genetics Unit; Reino Unido
Fil: Lee-Kirsch, Min Ae. Dresden University Faculty Of Medicine And University Hospital Carl Gustav Carus; Alemania
description 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.
publishDate 2015
dc.date.none.fl_str_mv 2015-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/125569
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
0021-9738
1558-8238
CONICET Digital
CONICET
url http://hdl.handle.net/11336/125569
identifier_str_mv 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
0021-9738
1558-8238
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.jci.org/articles/view/78001
info:eu-repo/semantics/altIdentifier/doi/10.1172/JCI78001
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society for Clinical Investigation
publisher.none.fl_str_mv American Society for Clinical Investigation
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1846781506270265344
score 12.982451