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
.jpg)
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/125569
Ver los metadatos del registro completo
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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 |
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info:eu-repo/semantics/altIdentifier/url/https://www.jci.org/articles/view/78001 info:eu-repo/semantics/altIdentifier/doi/10.1172/JCI78001 |
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info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
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openAccess |
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https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
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application/pdf application/pdf |
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American Society for Clinical Investigation |
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American Society for Clinical Investigation |
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reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
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Consejo Nacional de Investigaciones Científicas y Técnicas |
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CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
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dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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12.982451 |