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Defective removal of ribonucleotides from DNA promotes systemic autoimmunity
- Source :
- CONICET Digital (CONICET), Consejo Nacional de Investigaciones Científicas y Técnicas, instacron:CONICET, Europe PubMed Central, The journal of clinical investigation 125(1), 413-424 (2014). doi:10.1172/JCI78001, SEDICI (UNLP), Universidad Nacional de La Plata, instacron:UNLP
- Publication Year :
- 2015
- Publisher :
- American Society for Clinical Investigation, 2015.
-
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.<br />La lista completa de autores que integran el documento puede consultarse en el archivo<br />Instituto de Física de Líquidos y Sistemas Biológicos
- Subjects :
- Heterozygote
DNA Repair
RNase P
DNA repair
DNA damage
Biología
Ribonucleotide excision repair
DNA Mutational Analysis
Ribonuclease H
Gene Expression
purl.org/becyt/ford/3.5 [https]
genetics [Lupus Erythematosus, Systemic]
Autoimmunity
Biology
metabolism [Pyrimidine Dimers]
medicine.disease_cause
genetics [Pyrimidine Dimers]
chemistry.chemical_compound
Rnase H2
metabolism [Interferon Type I]
medicine
Humans
ddc:610
RNase H
Aicardi-Goutieres Syndrome
Gene
Cells, Cultured
genetics [Ribonuclease H]
Cell Proliferation
Syndrome AGS
Mutation
ribonuclease HII
Lupus Erythematosus
genetics [Autoimmunity]
genetics [Interferon Type I]
General Medicine
Molecular biology
Aicardi Syndrome
chemistry
Pyrimidine Dimers
Cardiovascular and Metabolic Diseases
Interferon Type I
biology.protein
purl.org/becyt/ford/3 [https]
DNA
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- CONICET Digital (CONICET), Consejo Nacional de Investigaciones Científicas y Técnicas, instacron:CONICET, Europe PubMed Central, The journal of clinical investigation 125(1), 413-424 (2014). doi:10.1172/JCI78001, SEDICI (UNLP), Universidad Nacional de La Plata, instacron:UNLP
- Accession number :
- edsair.doi.dedup.....462073bd56292581219ec18b2eb88b0b