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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
10
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pubmed:dateCreated |
2010-10-8
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pubmed:abstractText |
In the autoimmune syndrome rheumatoid arthritis (RA), T cells and T-cell precursors have age-inappropriate shortening of telomeres and accumulate deoxyribonucleic acid (DNA) double strand breaks. Whether damaged DNA elicits DNA repair activity and how this affects T-cell function and survival is unknown. Here, we report that naïve and resting T cells from RA patients are susceptible to undergo apoptosis. In such T cells, unrepaired DNA stimulates a p53-ataxia telangiectasia mutated-independent pathway involving the non-homologous-end-joining protein DNA-protein kinase catalytic subunit (DNA-PKcs). Upregulation of DNA-PKcs transcription, protein expression and phosphorylation in RA T cells co-occurs with diminished expression of the Ku70/80 heterodimer, limiting DNA repair capacity. Inhibition of DNA-PKcs kinase activity or gene silencing of DNA-PKcs protects RA T cells from apoptosis. DNA-PKcs induces T-cell death by activating the JNK pathway and upregulating the apoptogenic BH3-only proteins Bim and Bmf. In essence, in RA, the DNA-PKcs-JNK-Bim/Bmf axis transmits genotoxic stress into shortened survival of naïve resting T cells, imposing chronic proliferative turnover of the immune system and premature immunosenescence. Therapeutic blockade of the DNA-PK-dependent cell-death machinery may rejuvenate the immune system in RA.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
1757-4684
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:volume |
2
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
415-27
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pubmed:dateRevised |
2011-10-3
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pubmed:meshHeading |
pubmed-meshheading:20878914-Adaptor Proteins, Signal Transducing,
pubmed-meshheading:20878914-Aged,
pubmed-meshheading:20878914-Apoptosis,
pubmed-meshheading:20878914-Apoptosis Regulatory Proteins,
pubmed-meshheading:20878914-Arthritis, Rheumatoid,
pubmed-meshheading:20878914-Catalytic Domain,
pubmed-meshheading:20878914-DNA Repair,
pubmed-meshheading:20878914-DNA-Activated Protein Kinase,
pubmed-meshheading:20878914-Female,
pubmed-meshheading:20878914-Gene Silencing,
pubmed-meshheading:20878914-Humans,
pubmed-meshheading:20878914-Immune Tolerance,
pubmed-meshheading:20878914-MAP Kinase Kinase 4,
pubmed-meshheading:20878914-Male,
pubmed-meshheading:20878914-Membrane Proteins,
pubmed-meshheading:20878914-Middle Aged,
pubmed-meshheading:20878914-Proto-Oncogene Proteins,
pubmed-meshheading:20878914-Signal Transduction,
pubmed-meshheading:20878914-T-Lymphocytes
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pubmed:year |
2010
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pubmed:articleTitle |
DNA-dependent protein kinase catalytic subunit mediates T-cell loss in rheumatoid arthritis.
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pubmed:affiliation |
Department of Medicine, Immunology and Rheumatology, Stanford University, Stanford, CA, USA.
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pubmed:publicationType |
Journal Article,
Research Support, N.I.H., Extramural
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