Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis.
Open accessAbstract
In rheumatoid arthritis (RA), dysfunctional T cells sustain chronic inflammatory immune responses in the synovium. Even unprimed T cells are under excessive replication pressure, suggesting an intrinsic defect in T cell regeneration. In naive CD4 CD45RA+ T cells from RA patients, DNA damage load and apoptosis rates were markedly higher than in controls; repair of radiation-induced DNA breaks was blunted and delayed. DNA damage was highest in newly diagnosed untreated patients. RA T cells failed to produce sufficient transcripts and protein of the DNA repair kinase ataxia telangiectasia (AT) mutated (ATM). NBS1, RAD50, MRE11, and p53 were also repressed. ATM knockdown mimicked the biological effects characteristic for RA T cells. Conversely, ATM overexpression reconstituted DNA repair capabilities, response patterns to genotoxic stress, and production of MRE11 complex components and rescued RA T cells from apoptotic death. In conclusion, ATM deficiency in RA disrupts DNA repair and renders T cells sensitive to apoptosis. Apoptotic attrition of naive T cells imposes lymphopenia-induced proliferation, leading to premature immunosenescence and an autoimmune-biased T cell repertoire. Restoration of DNA repair mechanisms emerges as an important therapeutic target in RA.
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T cells from rheumatoid arthritis patients are ATM-deficient, accumulate DNA breaks, and fail to repair radiation-induced DNA lesions efficiently.
“Patients with RA have ATM-deficient T cells which accumulate DNA breaks and fail to efficiently repair radiation-induced DNA lesions [74].”
From T-cell aging in rheumatoid arthritis (2014) · cites this paper as [74]
Forcing overexpression of ATM reverses the abnormal phenotype of rheumatoid arthritis T cells.
“Forced overexpression of ATM rescues the abnormal phenotype of the RA T cells.”
From T-cell aging in rheumatoid arthritis (2014) · cites this paper as [74]
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References 46 · Cited by 159
- Authors
- Shao, L., Fujii, H., Colmegna, I., Oishi, H., Goronzy, J. J., & Weyand, C. M.
- Affiliations
- Emory University (US)
- Corresponding author
- Weyand, Cornelia M.
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2009-05-18
- Volume
- 206
- Issue
- 6
- Pages
- 1435-1449
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2715066
- OpenAlex
- W2113206255
- Cited by
- 159
- References
- 46
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 5 · 2023: 9 · 2022: 15 · 2021: 8 · 2020: 8 · 2019: 10 · 2018: 6 · 2017: 12 · 2016: 12 · 2015: 9 · 2014: 4 · 2013: 11 · 2012: 8
- FWCI
- 4.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR000454, R01-AI44142)
- National Institute on Aging (R01AG015043, R01AG15043)
- National Heart, Lung, and Blood Institute (R01HL117913)
- National Eye Institute (R01EY011916, R01 EY 11916)
- National Institute of Allergy and Infectious Diseases (R01AI044142, U19-AI57266, R01AI44142, R01AI108906, R56AI044142, U19AI057266)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR041974, R01 AR 41974, R01AR042527, R01AR42527)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- rheumatoid arthritis, ATM, DNA repair, T cell apoptosis, naive CD4+ T cells, DNA damage, immunosenescence, Mre11 complex, NBS1, RAD50, p53, lymphopenia, synovitis, genotoxic stress
- MeSH terms
- MRE11 Homologue Protein, Adult, Arthritis, Rheumatoid, DNA Damage, DNA Repair, DNA-Binding Proteins, Female, Gene Expression Regulation, Humans, Middle Aged, Recombinant Fusion Proteins, T-Lymphocytes, CD4 Antigens, Tumor Suppressor Protein p53, Apoptosis, Protein Serine-Threonine Kinases, Leukocyte Common Antigens, Cell Cycle Proteins, Comet Assay, Tumor Suppressor Proteins, Ataxia Telangiectasia Mutated Proteins
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