Defective removal of ribonucleotides from DNA promotes systemic lupus erythematosus

CLAUDIA GÜNTHER; BARBARA KIND; MARTIN A.M. REIJNS; NICOLE BERNDT; MANUEL MARTINEZ-BUENO; CHRISTINE WOLF; VICTORIA TÜNGLER; CHARA OSVALDO; SOPHIA BLUM; CLAUDIA KRUG; SCHMIDT FRANZISKA; KRETSCHMER STEFANIE; SARAH KOSS; TORSTEN WITTE; MARTIN ARINGER; ANNEGRET KUHN; INGA MELCHERS; DIMITRA ALEXOPOULOU; KARSTEN CONRAD; ANDREAS DAHL; AXEL ROERS; MARTA E. ALARCON-RIQUELME; ANDREW P. JACKSON; LEE-KIRSCH MIN AE

Ulm

Congreso; 42nd Annual Meeting of the Arbeitsgemeinschaft Dermatologische Forschung (ADF); 2015

Arbeitsgemeinschaft Dermatologische Forschung (ADF)

ystemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease in which environmentalexposures like virus infection and UV-irradiation trigger activation of the innate and adaptive immunesystem in genetically predisposed individuals. Heterozygous mutations of the human 3? repairexonuclease 1 are associated with SLE. Biallelic mutations in this enzyme cause Aicardi-Goutiressyndrom, a rare encephalopathy with clinical manifestations similar to SLE that can also be based onbiallelic mutations in ribonuclease H2 (RNaseH2). We therefore asked for associations of mutations inRNaseH2 and SLE. RNaseH2 is responsible for the removal of misincorporated ribonucleotides fromDNA and is indispensable for genome surveillance. Here we demonstrate a genetic association for rareRNase H2 sequence variants with SLE. Such mutations impair RNase H2 function and result inaccumulation of ribonucleotides in genomic DNA in AGS and SLE patient fibroblasts. The ensuingchronic low level DNA damage triggers a DNA damage response characterized by constitutive p53phosphorylation and senescence. Patient fibroblasts proliferated slower than fibroblasts from healthyindividuals and showed impairment of cell cycle progression. In addition, these primary cells showconstitutive up-regulation of interferon-stimulated genes and an enhanced type I interferon responseto the nucleic acid poly(I:C) and UV light-irradiation. Moreover, UV-induced cyclobutane pyrimidinedimer formation is significantly enhanced in ribonucleotide-containing DNA, providing a mechanismfor photosensitivity in RNase H2-associated SLE. Collectively, our findings implicate RNase H2 in thepathogenesis of SLE, and suggest a role of DNA damage-associated pathways in increased basal andUV induced type I IFN expression for the initiation of autoimmunity