ArticleProceedings of the National Academy of Sciences of the United States of America2007
ATM deficiency impairs thymocyte maturation because of defective resolution of T cell receptor alpha locus coding end breaks.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 70 citations in OpenAlex.
- Hematopoietic Stem Cell Transplantation Restores Naïve T-Cell Populations inFrontiers in immunology · 2019Trial
- Immune perturbations in human pancreas lymphatic tissues prior to and after type 1 diabetes onset.Nature communications · 2025Article
- Transcriptional profiling of peripheral blood mononuclear cells identifies inflammatory phenotypes in Ataxia Telangiectasia.Orphanet journal of rare diseases · 2024Article
- T Cell Repertoire Abnormality in Immunodeficiency Patients with DNA Repair and Methylation Defects.Journal of clinical immunology · 2022Article
- A novel, ataxic mouse model of ataxia telangiectasia caused by a clinically relevant nonsense mutation.eLife · 2021Article
- Mechanisms Underlying the Suppression of Chromosome Rearrangements by Ataxia-Telangiectasia Mutated.Genes · 2021Review
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- Deficiency of ataxia-telangiectasia mutated kinase modulates functional and biochemical parameters of the heart in response to Western-type diet.American journal of physiology. Heart and circulatory physiology · 2021Article
- Survival and Functional Immune Reconstitution After Haploidentical Stem Cell Transplantation inFrontiers in immunology · 2021Article
- Ataxia-telangiectasia mutated is required for the development of protective immune memory after influenza A virus infection.American journal of physiology. Lung cellular and molecular physiology · 2019Article
- The histone methyltransferase Setd2 is indispensable for V(D)J recombination.Nature communications · 2019Article
- Elevated IgM levels as a marker for a unique phenotype in patients with Ataxia telangiectasia.BMC pediatrics · 2018Article
- Atm reactivation reverses ataxia telangiectasia phenotypes in vivo.Cell death & disease · 2018Article
- Absence of ERK5/MAPK7 delays tumorigenesis in Atm-/- mice.Oncotarget · 2016Article
- The ATM Kinase Restrains Joining of Both VDJ Signal and Coding Ends.Journal of immunology (Baltimore, Md. : 1950) · 2016Article
- Programmed DNA breaks in lymphoid cells: repair mechanisms and consequences in human disease.Immunology · 2016Review
- DNA Repair Cofactors ATMIN and NBS1 Are Required to Suppress T Cell Activation.PLoS genetics · 2015Article
- IL-7 coordinates proliferation, differentiation and Tcra recombination during thymocyte β-selection.Nature immunology · 2015Article
- Disturbed B and T cell homeostasis and neogenesis in patients with ataxia telangiectasia.Journal of clinical immunology · 2014Article
- T-cell-specific deletion of Mof blocks their differentiation and results in genomic instability in mice.Mutagenesis · 2013Article
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
The ATM (ataxia telangiectasia mutated) protein plays a central role in sensing and responding to DNA double-strand breaks. Lymphoid cells are unique in undergoing physiologic double-strand breaks in the processes of Ig class switch recombination and T or B cell receptor V(D)J recombination, and a role for ATM in these processes has been suggested by clinical observations in ataxia telangiectasia patients as well as in engineered mice with mutations in the Atm gene. We demonstrate here a defect in thymocyte maturation in ATM-deficient mice that is associated with decreased efficiency in V-J rearrangement of the endogenous T cell receptor (TCR)alpha locus, accompanied by increased frequency of unresolved TCR Jalpha coding end breaks. We also demonstrate that a functionally rearranged TCRalphabeta transgene is sufficient to restore thymocyte maturation, whereas increased thymocyte survival by bcl-2 cannot improve TCRalpha recombination and T cell development. These data indicate a direct role for ATM in TCR gene recombination in vivo that is critical for surface TCR expression in CD4(+)CD8(+) cells and for efficient thymocyte selection. We propose a unified model for the two major clinical characteristics of ATM deficiency, defective T cell maturation and increased genomic instability, frequently affecting the TCRalpha locus. In the absence of ATM, delayed TCRalpha coding joint formation results both in a reduction of alphabeta TCR-expressing immature cells, leading to inefficient thymocyte selection, and in accumulation of unstable open chromosomal DNA breaks, predisposing to TCRalpha locus-associated chromosomal abnormalities.
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