Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products

Song Zhao, Yi-Chinn Weng, Shyng-Shiou F. Yuan, Yi-Tzu Lin, Hao-Chi Hsu, Suh-Chin J. Lin, Elvira Gerbino, Mei-hua Song, Malgorzata Z. Zdzienicka, Richard A. Gatti, Jerry W. Shay, Yael Ziv, Yosef Shiloh and Eva Y.-H. P. Lee ()
Additional contact information
Song Zhao: The University of Texas Health Science Center at San Antonio
Yi-Chinn Weng: The University of Texas Health Science Center at San Antonio
Shyng-Shiou F. Yuan: The University of Texas Health Science Center at San Antonio
Yi-Tzu Lin: The University of Texas Health Science Center at San Antonio
Hao-Chi Hsu: The University of Texas Health Science Center at San Antonio
Suh-Chin J. Lin: The University of Texas Health Science Center at San Antonio
Elvira Gerbino: The University of Texas Health Science Center at San Antonio
Mei-hua Song: The University of Texas Health Science Center at San Antonio
Malgorzata Z. Zdzienicka: Leiden University, LUMC
Richard A. Gatti: University of California Los Angeles
Jerry W. Shay: The University of Texas Southwestern Medical Center
Yael Ziv: Sackler School of Medicine, Tel Aviv University
Yosef Shiloh: Sackler School of Medicine, Tel Aviv University
Eva Y.-H. P. Lee: The University of Texas Health Science Center at San Antonio

Nature, 2000, vol. 405, issue 6785, 473-477

Abstract: Abstract Ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are recessive genetic disorders with susceptibility to cancer and similar cellular phenotypes1. The protein product of the gene responsible for A-T, designated ATM, is a member of a family of kinases characterized by a carboxy-terminal phosphatidylinositol 3-kinase-like domain2,3. The NBS1 protein is specifically mutated in patients with Nijmegen breakage syndrome and forms a complex with the DNA repair proteins Rad50 and Mre114,5,6,7. Here we show that phosphorylation of NBS1, induced by ionizing radiation, requires catalytically active ATM. Complexes containing ATM and NBS1 exist in vivo in both untreated cells and cells treated with ionizing radiation. We have identified two residues of NBS1, Ser 278 and Ser 343 that are phosphorylated in vitro by ATM and whose modification in vivo is essential for the cellular response to DNA damage. This response includes S-phase checkpoint activation, formation of the NBS1/Mre11/Rad50 nuclear foci and rescue of hypersensitivity to ionizing radiation. Together, these results demonstrate a biochemical link between cell-cycle checkpoints activated by DNA damage and DNA repair in two genetic diseases with overlapping phenotypes.

Date: 2000
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DOI: 10.1038/35013083

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