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Distinct domains in Nbs1 regulate irradiation-induced checkpoints and apoptosis

  1. Author:
    Difilippantonio, S.
    Celeste, A.
    Kruhlak, M.
    Lee, Y.
    Difilippantonio, M. J.
    Feigenbaum, L.
    Jackson, S. P.
    McKinnon, P. J.
    Nussenzweig, A.

  2. Author Address

    NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. St Jude Childrens Hosp, Dept Genet & Tumor Cell Biol, Memphis, TN 38105 USA. Natl Canc Inst, Frederick Canc Res & Dev Ctr, SAIC Frederick, Ft Detrick, MD 21702 USA. Univ Cambridge, Dept Zool, Cambridge CB2 1QN, England. Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Cambridge CB2 1QN, England.;Nussenzweig, A, NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA.;andre_nussenzweig@nih.gov
    1. Year: 2007
    2. Date: May
  2. Journal: Journal of Experimental Medicine
    1. 204
    2. 5
    3. Pages: 1003-1011
  4. Type of Article: Article
  5. ISSN: 0022-1007
  1. Abstract:

    The chromosomal instability syndromes Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT) share many overlapping phenotypes, including cancer predisposition, radiation sensitivity, cell-cycle checkpoint defects, immunodeficiency, and gonadal dysfunction. The NBS protein Nbs1 is not only a downstream target of AT mutated (ATM) kinase but also acts upstream, promoting optimal ATM activation, ATM recruitment to breaks, and ATM accessibility to substrates. By reconstituting Nbs1 knockout mice with bacterial artificial chromosomes, we have assessed the contribution of distinct regions of Nbs1 to the ATM-dependent DNA damage response. We fi nd that T cell and oocyte development, as well as DNA damage-induced G2/M and S phase checkpoint arrest and radiation survival are dependent on the N-terminal forkhead-associated domain, but not on the principal residues phosphorylated by ATM (S278 and S343) or on the evolutionarily conserved C-terminal region of Nbs1. However, the C-terminal region regulates irradiation-induced apoptosis. These studies provide insight into the complex interplay between Nbs1 and ATM in the DNA damage response.

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  2. DOI: 10.1084/jem.20070319
  3. View record in Web of Science®
  4. WOS: 000246467600006

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