Defective DNA repair and chromatin organization in patients with quiescent systemic lupus erythematosus.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
['Souliotis|Vassilis L|VL|', 'Vougas|Konstantinos|K|', 'Gorgoulis|Vassilis G|VG|', 'Sfikakis|Petros P|PP|']
D000328:Adult D017209:Apoptosis D015153:Blotting, Western D002843:Chromatin D004260:DNA Repair D005260:Female D006801:Humans D008180:Lupus Erythematosus, Systemic D008297:Male D008875:Middle Aged D016133:Polymerase Chain Reaction D055815:Young Adult
Chromatin organization Systemic lupus erythematosus Apoptosis Nucleotide excision repair DNA double-strand breaks repair Histone deacetylase inhibitor