Role of Nbs1 in the activation of the Atm kinase revealed in humanized mouse models
- PMID: 15965469
- DOI: 10.1038/ncb1270
Role of Nbs1 in the activation of the Atm kinase revealed in humanized mouse models
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.
Comment in
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Nbs1 moving up in the world.Nat Cell Biol. 2005 Jul;7(7):648-50. doi: 10.1038/ncb0705-648. Nat Cell Biol. 2005. PMID: 15990895 No abstract available.
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