IMR Press / FBL / Volume 6 / Issue 3 / DOI: 10.2741/takeda

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

Open Access Article
Autoantibodies against DNA double-strand break repair proteins
Show Less
1 Program in Gene Regulation, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA, USA

Academic Editor: Robert Hoffman

Front. Biosci. (Landmark Ed) 2001, 6(3), 1412–1422; https://doi.org/10.2741/takeda
Published: 1 November 2001
(This article belongs to the Special Issue Pathogenesis of systemic lupus erythematosus)
Abstract

Autoantibodies against cellular components are commonly present in sera from patients with systemic rheumatic diseases and may play an important role in pathogenesis. The Ku protein was recognized 20 years ago as a major target of autoantibodies in a subset of Japanese patients with scleroderma-polymyositis overlap syndrome, and anti-Ku antibodies have since been shown to occur in 10-20% of patients with these and other systemic rheumatic diseases, including systemic lupus erythematosus. Ku functions physiologically in the repair of DNA double-strand breaks, where it carries out the initial recognition of damaged DNA ends. The three dimensional structure of the Ku-DNA complex has recently been solved, and helps illuminate the relationship between the autoimmune epitopes and other features of the protein. In addition to Ku, three other polypeptides in the same DNA repair pathway have more recently been identified as autoantigens: the DNA-dependent protein kinase catalytic subunit, DNA ligase IV, and XRCC4. Two hypotheses have been invoked to explain the ability of these proteins to elicit an autoimmune response in susceptible individuals. One is that DNA damage induces formation of nucleoprotein complexes that present novel composite or conformational epitopes. The other is that cleavage of these proteins by caspases or Granzyme B leads to presentation of immunocryptic peptides capable of stimulating autoreactive T lymphocytes. In the case of DNA double-strand break repair proteins, there is evidence that both of these mechanisms may be at work. Because of their role in the maintenance of genome stability, DNA double-strand break repair proteins have been the subject of intense study, and a wealth of new structural, biochemical and functional information makes them excellent models for investigation of the humoral autoimmune response.

Share
Back to top