Abstract
Ataxia telangiectasia (A-T) is a disorder characterized by cerebellar degeneration, immunodeficiency, genomic instability and genetic predisposition to lymphoid malignancies with translocations involving antigen receptor loci. The Ataxia Telangiectasia Mutated gene encodes the ATM kinase, a central transducer of DNA damage signals. Until recently, the etiology of the lymphoid phenotype in A-T patients and the mechanisms by which ATM ensures normal repair of DNA double strand break (DSB) intermediates during antigen receptor diversification reactions remained poorly understood. Last year, Bredemeyer et al. (Nature 2006; 442:466-70) demonstrated that ATM stabilizes chromosomal V(D)J recombination DSB intermediates, facilitates DNA end joining and prevents broken DNA ends from participating in chromosome deletions, inversions and translocations. A more recent study by Callen et al. (Cell 2007; 130:63-75) highlighted the importance of ATM-mediated checkpoints in blocking the long-term persistence and transmission of un-repaired DSBs in developing lymphocytes. Collectively, these results have provided complementary mechanistic insights into ATM functions in V(D)J recombination that can account for the lymphoid tumor-prone phenotype associated with A-T.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / physiology*
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Chromosome Aberrations
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DNA Breaks, Double-Stranded*
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DNA Repair / physiology*
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Gene Rearrangement / physiology
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Genes, cdc
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Homeodomain Proteins / physiology
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Humans
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Lymphocytes / cytology
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Lymphoproliferative Disorders / enzymology
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Lymphoproliferative Disorders / genetics
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Lymphoproliferative Disorders / physiopathology
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Models, Immunological
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Nuclear Proteins / physiology
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / physiology*
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Receptors, Antigen / genetics
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Recombination, Genetic / physiology
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Signal Transduction / physiology
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Tumor Suppressor Proteins / deficiency
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / physiology*
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VDJ Recombinases / physiology
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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Homeodomain Proteins
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Nuclear Proteins
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RAG2 protein, human
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Receptors, Antigen
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Tumor Suppressor Proteins
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RAG-1 protein
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases
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VDJ Recombinases