IFLYSIB   05383
INSTITUTO DE FISICA DE LIQUIDOS Y SISTEMAS BIOLOGICOS
Unidad Ejecutora - UE
artículos
Título:
Defective removal of ribonucleotides from DNA promotes systemic autoimmunity
Autor/es:
CLAUDIA GÜNTHER; BARBARA KIND; MARTIN A.M. REIJNS; NICOLE BERNDT; MANUEL MARTINEZ-BUENO; CHRISTINE WOLF; VICTORIA TÜNGLER; OSVALDO CHARA; YOUNG AE LEE; NORBERT HÜBNER; LOUISE BICKNELL; SOPHIA BLUM; CLAUDIA KRUG; FRANZISKA SCHMIDT; STEFANIE KRETSCHMER; SARAH KOSS; KATY R. ASTELL; GEORGIA RAMANTANI; ANJA BAUERFEIND; DAVID L. MORRIS; DEBORAH S. CUNNINGHAME GRAHAM; DORYEN BUBECK; ANDREA LEITCH; STUART H. RALSTON; ELIZABETH A. BLACKBURN; MANFRED GAHR; TORSTEN WITTE; TIMOTHY J. VYSE; INGA MELCHERS; ELISABETH MANGOLD; MARKUS M. NÖTHEN; MARTIN ARINGER; ANNEGRET KUHN; KIRSTEN LÜTHKE; LEONORE UNGER; ANNETTE BLEY; ALICE LORENZI; JOHN D. ISAACS; DIMITRA ALEXOPOULOU; KARSTEN CONRAD; ANDREAS DAHL; AXEL ROERS; MARTA E. ALARCON-RIQUELME; ANDREW P. JACKSON; MIN AE LEE-KIRSCH
Revista:
JOURNAL OF CLINICAL INVESTIGATION
Editorial:
AMER SOC CLINICAL INVESTIGATION INC
Referencias:
Lugar: Ann Arbor, Michigan; Año: 2015 vol. 125 p. 413 - 424
ISSN:
0021-9738
Resumen:
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.