Format

Send to

Choose Destination
Arthritis Res Ther. 2016 Aug 4;18(1):182. doi: 10.1186/s13075-016-1081-3.

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

Author information

1
Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece. vls@eie.gr.
2
Joint Rheumatology Program and First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece. vls@eie.gr.
3
Biomedical Research Foundation, Academy of Athens, Athens, Greece.
4
Molecular Carcinogenesis Group, Department of Histology and Embryology, National and Kapodistrian University of Athens Medical School, Athens, Greece.
5
Joint Rheumatology Program and First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece.

Abstract

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.

KEYWORDS:

Apoptosis; Chromatin organization; DNA double-strand breaks repair; Histone deacetylase inhibitor; Nucleotide excision repair; Systemic lupus erythematosus

PMID:
27492607
PMCID:
PMC4973109
DOI:
10.1186/s13075-016-1081-3
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center