Identification of human autoantibodies to the DNA ligase IV/XRCC4 complex and mapping of an autoimmune epitope to a potential regulatory region

Kyung Jong Lee, Xingwen Dong, Jingsong Wang, Yoshihiko Takeda, William S. Dynan

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35 Citations (Scopus)

Abstract

The nonhomologous end-joining pathway is the principal mechanism for repair of ionizing radiation-induced, double-strand breaks in mammalian cells. Three polypeptides in this pathway, including the two subunits of Ku protein and the catalytic subunit of the DNA-dependent protein kinase, are known targets of autoantibodies in systemic rheumatic diseases. Here we show that two additional polypeptides in the pathway, DNA ligase IV and XRCC4, are also targets of autoantibodies. These Abs were present in 20% of patients with systemic lupus erythematosus and overlap syndrome. Previous work has shown that XRCC4 is subject to radiation-induced post-translational modification, including phosphorylation by DNA-dependent protein kinase and cleavage by caspase 3. We mapped a major autoimmune epitope in XRCC4 and found that it encompassed a DNA-dependent protein kinase phosphorylation site, which is located at serine 260; that it was adjacent to a site for caspase 3, which cleaves after residue 265; and that it also spanned a site for the inflammatory protease, granzyme B, which cleaves after residue 254. The finding that five different polypeptides in the nonhomologous end-joining pathway are potential targets of autoantibodies together with the observation that one of the autoimmune epitopes in XRCC4 coincides with a sequence that is a nexus for radiation-induced regulatory events suggest that exposure to agents that introduce DNA double-strand breaks may be one of the factors that influences the development of an autoimmune response in susceptible individuals.

Original languageEnglish (US)
Pages (from-to)3413-3421
Number of pages9
JournalJournal of Immunology
Volume169
Issue number6
StatePublished - Sep 15 2002

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DNA-Activated Protein Kinase
Epitope Mapping
Forensic Anthropology
Nucleic Acid Regulatory Sequences
Autoantibodies
Caspase 3
Peptides
Epitopes
Phosphorylation
Catalytic DNA
Radiation
Granzymes
Double-Stranded DNA Breaks
Protein Subunits
Post Translational Protein Processing
Ionizing Radiation
Rheumatic Diseases
Autoimmunity
Systemic Lupus Erythematosus
Serine

ASJC Scopus subject areas

  • Immunology

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Identification of human autoantibodies to the DNA ligase IV/XRCC4 complex and mapping of an autoimmune epitope to a potential regulatory region. / Lee, Kyung Jong; Dong, Xingwen; Wang, Jingsong; Takeda, Yoshihiko; Dynan, William S.

In: Journal of Immunology, Vol. 169, No. 6, 15.09.2002, p. 3413-3421.

Research output: Contribution to journalArticle

Lee, Kyung Jong ; Dong, Xingwen ; Wang, Jingsong ; Takeda, Yoshihiko ; Dynan, William S. / Identification of human autoantibodies to the DNA ligase IV/XRCC4 complex and mapping of an autoimmune epitope to a potential regulatory region. In: Journal of Immunology. 2002 ; Vol. 169, No. 6. pp. 3413-3421.
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