Defective removal of ribonucleotides from DNA promotes systemic autoimmunity

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 auto...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autor principal: Chara, Osvaldo
Formato: Articulo
Lenguaje:Inglés
Publicado: 2015
Materias:
Biología
Aicardi Syndrome
Mutation
Syndrome AGS
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/86202
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-86202
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Biología
Aicardi Syndrome
Mutation
Syndrome AGS
spellingShingle Biología
Aicardi Syndrome
Mutation
Syndrome AGS
Chara, Osvaldo
Defective removal of ribonucleotides from DNA promotes systemic autoimmunity
topic_facet Biología
Aicardi Syndrome
Mutation
Syndrome AGS
description 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.
format Articulo
Articulo
author Chara, Osvaldo
author_facet Chara, Osvaldo
author_sort Chara, Osvaldo
title Defective removal of ribonucleotides from DNA promotes systemic autoimmunity
title_short Defective removal of ribonucleotides from DNA promotes systemic autoimmunity
title_full Defective removal of ribonucleotides from DNA promotes systemic autoimmunity
title_fullStr Defective removal of ribonucleotides from DNA promotes systemic autoimmunity
title_full_unstemmed Defective removal of ribonucleotides from DNA promotes systemic autoimmunity
title_sort defective removal of ribonucleotides from dna promotes systemic autoimmunity
publishDate 2015
url http://sedici.unlp.edu.ar/handle/10915/86202
work_keys_str_mv AT charaosvaldo defectiveremovalofribonucleotidesfromdnapromotessystemicautoimmunity
bdutipo_str Repositorios
_version_ 1764820489426960387

Ejemplares similares