title: Defective DNA repair and chromatin organization in patients with quiescent systemic lupus erythematosus.
abstract: Excessive autoantibody production characterizing systemic lupus erythematosus (SLE) occurs irrespective of the disease's clinical status and is linked to increased lymphocyte apoptosis. Herein, we tested the hypothesis that defective DNA damage repair contributes to increased apoptosis in SLE.
  
  
  
  We evaluated nucleotide excision repair at the N-ras locus, DNA double-strand breaks repair and apoptosis rates in peripheral blood mononuclear cells from anti-dsDNA autoantibody-positive patients (six with quiescent disease and six with proliferative nephritis) and matched healthy controls following ex vivo treatment with melphalan. Chromatin organization and expression levels of DNA repair- and apoptosis-associated genes were also studied in quiescent SLE.
  
  
  
  Defective nucleotide excision repair and DNA double-strand breaks repair were found in SLE, with lupus nephritis patients showing higher DNA damage levels than those with quiescent disease. Melphalan-induced apoptosis rates were higher in SLE than control cells and correlated inversely with DNA repair efficiency. Chromatin at the N-ras locus was more condensed in SLE than controls, while treatment with the histone deacetylase inhibitor vorinostat resulted in hyperacetylation of histone H4, chromatin decondensation, amelioration of DNA repair efficiency and decreased apoptosis. Accordingly, genes involved in DNA damage repair and signaling pathways, such as DDB1, ERCC2, XPA, XPC, MRE11A, RAD50, PARP1, MLH1, MLH3, and ATM were significantly underexpressed in SLE versus controls, whereas PPP1R15A, BARD1 and BBC3 genes implicated in apoptosis were significantly overexpressed.
  
  
  
  Epigenetically regulated functional abnormalities of DNA repair machinery occur in SLE, regardless of clinical disease activity, and may promote lymphocyte apoptosis. Approaches to correct these abnormalities may be of therapeutic value in SLE.
authors: Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece. vls@eie.gr.|Joint Rheumatology Program and First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece. vls@eie.gr.
authors: Vassilis L
authors: VL
authors: Souliotis
authors: Biomedical Research Foundation, Academy of Athens, Athens, Greece.
authors: Konstantinos
authors: K
authors: Vougas
authors: Biomedical Research Foundation, Academy of Athens, Athens, Greece.|Molecular Carcinogenesis Group, Department of Histology and Embryology, National and Kapodistrian University of Athens Medical School, Athens, Greece.
authors: Vassilis G
authors: VG
authors: Gorgoulis
authors: Joint Rheumatology Program and First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece.
authors: Petros P
authors: PP
authors: Sfikakis
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000276:immunology; D015153:Blotting, Western; D002843:Chromatin / Q000276:immunology / Q000473:pathology*; D004260:DNA Repair / Q000276:immunology*; D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D002843:Chromatin
keywords: Apoptosis; Chromatin organization; DNA double-strand breaks repair; Histone deacetylase inhibitor; Nucleotide excision repair; Systemic lupus erythematosus