Article abstract
Nature Cell Biology 7, 675 - 685 (2005)
Published online: 19 June 2005 | doi:10.1038/ncb1270
Role of Nbs1 in the activation of the Atm kinase revealed in humanized mouse models
Simone Difilippantonio1, Arkady Celeste1, Oscar Fernandez-Capetillo1,9, Hua-Tang Chen1, Bernardo Reina San Martin2, Francois Van Laethem1, Yong-Ping Yang4, Galina V. Petukhova5, Michael Eckhaus6, Lionel Feigenbaum7, Katia Manova8, Michael Kruhlak1, R. Daniel Camerini-Otero5, Shyam Sharan4, Michel Nussenzweig2,3 & André Nussenzweig1
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.
- Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
- Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10021, USA
- Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10021, USA.
- Mouse Cancer Genetics Program, National Cancer Institute at Frederick, 1050 Boyles Street, Frederick, MD 21702, USA.
- Genetics and Biochemistry Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
- Division of Veterinary Resources, Office of Research Services, Office of the Director, National Institutes of Health, Bethesda, MD 20892, USA.
- SAIC-Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA.
- Molecular Cytology Core Facility and Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
- Present address: Genomic Instability Group, Molecular Oncology Program, Spanish National Cancer Center (CNIO) Madrid, 28029, Spain.
Correspondence to: André Nussenzweig1 e-mail: andre_nussenzweig@nih.gov
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