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


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.

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Figure 1: ATM is required for DNA damage-induced phosphorylation of NBS1.
Figure 2: Interaction between ATM and NBS1, in vivo and in vitro phosphorylation of NBS1 by ATM.
Figure 3: Expression of the full-length wild-type and NBS1 mutant proteins lacking phosphorylation site(s) in NBS1-LBI cells.
Figure 4: Radioresistant DNA synthesis (RDS) and sensitivity to ionizing radiation by expression of wild-type and NBS1 mutants lacking serine phosphorylation site(s).

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We thank W.-H. Lee, A. Tomkinson and members of their laboratories for discussion; A. Tomkinson, T. Boyer and P. Sung for critical reading; S.-Y. Lee for assistance on the manuscript; M. Chen for site-specific mutagenesis of ATM; Q. Du for the initial studies of ATM kinase; L. Zheng for technical advice; and S. Deb for the full-length human p53 cDNA. E.L. is supported by grants from NIH NINDS, Texas Advanced Research/Advanced Technology Program and NCI P01. S.Z. is supported by a DOD training grant.

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Correspondence to Eva Y.-H. P. Lee.

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Zhao, S., Weng, YC., Yuan, SS. et al. Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products. Nature 405, 473–477 (2000).

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