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Role of Nbs1 in the activation of the Atm kinase revealed in humanized mouse models

  1. Author:
    Difilippantonio, S.
    Celeste, A.
    Fernandez-Capetillo, O.
    Chen, H. T.
    San Martin, B. R.
    Van Laethem, F.
    Yang, Y. P.
    Petukhova, G. V.
    Eckhaus, M.
    Feigenbaum, L.
    Manova, K.
    Kruhlak, M.
    Camerini-Otero, R. D.
    Sharan, S.
    Nussenzweig, M.
    Nussenzweig, A.

  2. Author Address

    NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Rockefeller Univ, Lab Mol Immunol, New York, NY 10021 USA. Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA. NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. NIH, Div Vet Resources, Off Res Serv, Off Director, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Mem Sloan Kettering Canc Ctr, Mol Cytol Core Facil, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Program Mol Biol, New York, NY 10021 USA Nussenzweig, A, NCI, Expt Immunol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA
    1. Year: 2005
    2. Date: JUL
  2. Journal: Nature Cell Biology
    1. 7
    2. 7
    3. Pages: 675-U56
  4. Type of Article: Article
  1. 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

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External Sources

  1. View record in Web of Science®
  2. WOS: 000230190800011

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