Abstract
Nijmegen breakage syndrome (NBS) is a chromosomal fragility disorder that shares clinical and cellular features with ataxia telangiectasia. Here we demonstrate that Nbs1-null B cells are defective in the activation of ataxia-telangiectasia-mutated (Atm) in response to ionizing radiation, whereas ataxia-telangiectasia- and Rad3-related (Atr)-dependent signalling and Atm activation in response to ultraviolet light, inhibitors of DNA replication, or hypotonic stress are intact. Expression of the main human NBS allele rescues the lethality of Nbs1-/- mice, but leads to immunodeficiency, cancer predisposition, a defect in meiotic progression in females and cell-cycle checkpoint defects that are associated with a partial reduction in Atm activity. The Mre11 interaction domain of Nbs1 is essential for viability, whereas the Forkhead-associated (FHA) domain is required for T-cell and oocyte development and efficient DNA damage signalling. Reconstitution of Nbs1 knockout mice with various mutant isoforms demonstrates the biological impact of impaired Nbs1 function at the cellular and organismal level.
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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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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ATP-Binding Cassette Transporters / metabolism
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Acid Anhydride Hydrolases
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Animals
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Ataxia Telangiectasia Mutated Proteins
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B-Lymphocytes / immunology
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B-Lymphocytes / pathology
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Binding Sites / genetics
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Cell Cycle / genetics
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Cycle Proteins / physiology*
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Chromosome Aberrations
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Chromosome Breakage
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Chromosome Disorders / genetics
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Chromosome Disorders / metabolism
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Chromosome Disorders / pathology
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DNA Damage / genetics
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DNA Damage / physiology
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DNA Repair Enzymes
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DNA Replication / genetics
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DNA-Binding Proteins / metabolism*
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Disease Models, Animal*
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Female
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Genetic Predisposition to Disease / genetics
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Gonads / abnormalities
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Humans
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Immunoglobulin Class Switching / genetics
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Lymphoma, Non-Hodgkin / etiology
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Lymphoma, Non-Hodgkin / genetics
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MRE11 Homologue Protein
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Male
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Mice
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Mice, Knockout
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Mice, Transgenic
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Mutation
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Nuclear Proteins / physiology*
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism*
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Syndrome
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T-Lymphocytes / immunology
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T-Lymphocytes / pathology
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins / metabolism*
Substances
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ATP-Binding Cassette Transporters
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Cell Cycle Proteins
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DNA-Binding Proteins
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MRE11 protein, human
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Mre11a protein, mouse
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NBN protein, human
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Nijmegen breakage syndrome 1 protein, mouse
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Nuclear Proteins
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Atr protein, mouse
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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Protein Serine-Threonine Kinases
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MRE11 Homologue Protein
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Acid Anhydride Hydrolases
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Rad50 protein, mouse
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DNA Repair Enzymes