The Journal of Experimental Medicine
VeriKine-HS Human IFN-Beta
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Published online May 7, 2007
doi:10.1084/jem.20070319
The Journal of Experimental Medicine, Vol. 204, No. 5, 1003-1011
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Difilippantonio et al.
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BRIEF DEFINITIVE REPORT

 Distinct domains in Nbs1 regulate irradiation-induced checkpoints and apoptosis

Simone Difilippantonio1, Arkady Celeste1, Michael J. Kruhlak1, Youngsoo Lee2, Michael J. Difilippantonio3, Lionel Feigenbaum4, Stephen P. Jackson5, Peter J. McKinnon2, and André Nussenzweig1

1 Experimental Immunology Branch and 3 Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
2 Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105
4 SAIC-Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick MD 21702
5 Wellcome Trust/Cancer Research U.K. Gurdon Institute and the Department of Zoology, University of Cambridge, Cambridge CB2 1QN, England, UK

CORRESPONDENCE André Nussenzweig: andre_nussenzweig{at}nih.gov

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 find 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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