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-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.forename: Claudia
authors.initials: C
authors.lastname: Günther
authors.forename: Barbara
authors.initials: B
authors.lastname: Kind
authors.forename: Martin A M
authors.initials: MA
authors.lastname: Reijns
authors.forename: Nicole
authors.initials: N
authors.lastname: Berndt
authors.forename: Manuel
authors.initials: M
authors.lastname: Martinez-Bueno
authors.forename: Christine
authors.initials: C
authors.lastname: Wolf
authors.forename: Victoria
authors.initials: V
authors.lastname: Tüngler
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Chara
authors.forename: Young Ae
authors.initials: YA
authors.lastname: Lee
authors.forename: Norbert
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authors.lastname: Hübner
authors.forename: Louise
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authors.lastname: Bicknell
authors.forename: Sophia
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authors.lastname: Blum
authors.forename: Claudia
authors.initials: C
authors.lastname: Krug
authors.forename: Franziska
authors.initials: F
authors.lastname: Schmidt
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kretschmer
authors.forename: Sarah
authors.initials: S
authors.lastname: Koss
authors.forename: Katy R
authors.initials: KR
authors.lastname: Astell
authors.forename: Georgia
authors.initials: G
authors.lastname: Ramantani
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authors.lastname: Bauerfeind
authors.forename: David L
authors.initials: DL
authors.lastname: Morris
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Cunninghame Graham
authors.forename: Doryen
authors.initials: D
authors.lastname: Bubeck
authors.forename: Andrea
authors.initials: A
authors.lastname: Leitch
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Ralston
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Blackburn
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authors.lastname: Gahr
authors.forename: Torsten
authors.initials: T
authors.lastname: Witte
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Vyse
authors.forename: Inga
authors.initials: I
authors.lastname: Melchers
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mangold
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Martin
authors.initials: M
authors.lastname: Aringer
authors.forename: Annegret
authors.initials: A
authors.lastname: Kuhn
authors.forename: Kirsten
authors.initials: K
authors.lastname: Lüthke
authors.forename: Leonore
authors.initials: L
authors.lastname: Unger
authors.forename: Annette
authors.initials: A
authors.lastname: Bley
authors.forename: Alice
authors.initials: A
authors.lastname: Lorenzi
authors.forename: John D
authors.initials: JD
authors.lastname: Isaacs
authors.forename: Dimitra
authors.initials: D
authors.lastname: Alexopoulou
authors.forename: Karsten
authors.initials: K
authors.lastname: Conrad
authors.forename: Andreas
authors.initials: A
authors.lastname: Dahl
authors.forename: Axel
authors.initials: A
authors.lastname: Roers
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alarcon-Riquelme
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jackson
authors.forename: Min Ae
authors.initials: MA
authors.lastname: Lee-Kirsch
mesh_terms: D015551:Autoimmunity / Q000235:genetics*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D004260:DNA Repair; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D011740:Pyrimidine Dimers / Q000235:genetics / Q000378:metabolism*; D016914:Ribonuclease H / Q000235:genetics
chemical_list: D007370:Interferon Type I; D011740:Pyrimidine Dimers; C091139:ribonuclease HII; D016914:Ribonuclease H