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Defective removal of ribonucleotides from DNA promotes systemic autoimmunity

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Defective removal of ribonucleotides from DNA promotes systemic autoimmunity. / 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; Cunninghame Graham, Deborah S; 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.

in: J CLIN INVEST, Jahrgang 125, Nr. 1, 01.2015, S. 413-424.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Günther, C, Kind, B, Reijns, MAM, Berndt, N, Martinez-Bueno, M, Wolf, C, Tüngler, V, Chara, O, Lee, YA, Hübner, N, Bicknell, L, Blum, S, Krug, C, Schmidt, F, Kretschmer, S, Koss, S, Astell, KR, Ramantani, G, Bauerfeind, A, Morris, DL, Cunninghame Graham, DS, Bubeck, D, Leitch, A, Ralston, SH, Blackburn, EA, Gahr, M, Witte, T, Vyse, TJ, Melchers, I, Mangold, E, Nöthen, MM, Aringer, M, Kuhn, A, Lüthke, K, Unger, L, Bley, A, Lorenzi, A, Isaacs, JD, Alexopoulou, D, Conrad, K, Dahl, A, Roers, A, Alarcon-Riquelme, ME, Jackson, AP & Lee-Kirsch, MA 2015, 'Defective removal of ribonucleotides from DNA promotes systemic autoimmunity', J CLIN INVEST, Jg. 125, Nr. 1, S. 413-424. https://doi.org/10.1172/JCI78001

APA

Günther, C., Kind, B., Reijns, M. A. M., Berndt, N., Martinez-Bueno, M., Wolf, C., Tüngler, V., Chara, O., Lee, Y. A., Hübner, N., Bicknell, L., Blum, S., Krug, C., Schmidt, F., Kretschmer, S., Koss, S., Astell, K. R., Ramantani, G., Bauerfeind, A., ... Lee-Kirsch, M. A. (2015). Defective removal of ribonucleotides from DNA promotes systemic autoimmunity. J CLIN INVEST, 125(1), 413-424. https://doi.org/10.1172/JCI78001

Vancouver

Günther C, Kind B, Reijns MAM, Berndt N, Martinez-Bueno M, Wolf C et al. Defective removal of ribonucleotides from DNA promotes systemic autoimmunity. J CLIN INVEST. 2015 Jan;125(1):413-424. https://doi.org/10.1172/JCI78001

Bibtex

@article{76cda82d7b1a4786a738d3b3444731c1,
title = "Defective removal of ribonucleotides from DNA promotes systemic autoimmunity",
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-Gouti{\`e}res 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.",
keywords = "Autoimmunity, Cell Proliferation, Cells, Cultured, DNA Mutational Analysis, DNA Repair, Gene Expression, Heterozygote, Humans, Interferon Type I, Lupus Erythematosus, Systemic, Pyrimidine Dimers, Ribonuclease H",
author = "Claudia G{\"u}nther and Barbara Kind and Reijns, {Martin A M} and Nicole Berndt and Manuel Martinez-Bueno and Christine Wolf and Victoria T{\"u}ngler and Osvaldo Chara and Lee, {Young Ae} and Norbert H{\"u}bner and Louise Bicknell and Sophia Blum and Claudia Krug and Franziska Schmidt and Stefanie Kretschmer and Sarah Koss and Astell, {Katy R} and Georgia Ramantani and Anja Bauerfeind and Morris, {David L} and {Cunninghame Graham}, {Deborah S} and Doryen Bubeck and Andrea Leitch and Ralston, {Stuart H} and Blackburn, {Elizabeth A} and Manfred Gahr and Torsten Witte and Vyse, {Timothy J} and Inga Melchers and Elisabeth Mangold and N{\"o}then, {Markus M} and Martin Aringer and Annegret Kuhn and Kirsten L{\"u}thke and Leonore Unger and Annette Bley and Alice Lorenzi and Isaacs, {John D} and Dimitra Alexopoulou and Karsten Conrad and Andreas Dahl and Axel Roers and Alarcon-Riquelme, {Marta E} and Jackson, {Andrew P} and Lee-Kirsch, {Min Ae}",
year = "2015",
month = jan,
doi = "10.1172/JCI78001",
language = "English",
volume = "125",
pages = "413--424",
journal = "J CLIN INVEST",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "1",

}

RIS

TY - JOUR

T1 - Defective removal of ribonucleotides from DNA promotes systemic autoimmunity

AU - Günther, Claudia

AU - Kind, Barbara

AU - Reijns, Martin A M

AU - Berndt, Nicole

AU - Martinez-Bueno, Manuel

AU - Wolf, Christine

AU - Tüngler, Victoria

AU - Chara, Osvaldo

AU - Lee, Young Ae

AU - Hübner, Norbert

AU - Bicknell, Louise

AU - Blum, Sophia

AU - Krug, Claudia

AU - Schmidt, Franziska

AU - Kretschmer, Stefanie

AU - Koss, Sarah

AU - Astell, Katy R

AU - Ramantani, Georgia

AU - Bauerfeind, Anja

AU - Morris, David L

AU - Cunninghame Graham, Deborah S

AU - Bubeck, Doryen

AU - Leitch, Andrea

AU - Ralston, Stuart H

AU - Blackburn, Elizabeth A

AU - Gahr, Manfred

AU - Witte, Torsten

AU - Vyse, Timothy J

AU - Melchers, Inga

AU - Mangold, Elisabeth

AU - Nöthen, Markus M

AU - Aringer, Martin

AU - Kuhn, Annegret

AU - Lüthke, Kirsten

AU - Unger, Leonore

AU - Bley, Annette

AU - Lorenzi, Alice

AU - Isaacs, John D

AU - Alexopoulou, Dimitra

AU - Conrad, Karsten

AU - Dahl, Andreas

AU - Roers, Axel

AU - Alarcon-Riquelme, Marta E

AU - Jackson, Andrew P

AU - Lee-Kirsch, Min Ae

PY - 2015/1

Y1 - 2015/1

N2 - 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.

AB - 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.

KW - Autoimmunity

KW - Cell Proliferation

KW - Cells, Cultured

KW - DNA Mutational Analysis

KW - DNA Repair

KW - Gene Expression

KW - Heterozygote

KW - Humans

KW - Interferon Type I

KW - Lupus Erythematosus, Systemic

KW - Pyrimidine Dimers

KW - Ribonuclease H

U2 - 10.1172/JCI78001

DO - 10.1172/JCI78001

M3 - SCORING: Journal article

C2 - 25500883

VL - 125

SP - 413

EP - 424

JO - J CLIN INVEST

JF - J CLIN INVEST

SN - 0021-9738

IS - 1

ER -