ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway

Dae-Sik Lim, Seong-Tae Kim, Bo Xu, Richard S. Maser, Junyu Lin, John H.J. Petrini and Michael B. Kastan ()
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Dae-Sik Lim: Department of Hematology–Oncology St. Jude Children's Research Hospital
Seong-Tae Kim: Department of Hematology–Oncology St. Jude Children's Research Hospital
Bo Xu: Department of Hematology–Oncology St. Jude Children's Research Hospital
Richard S. Maser: Laboratory of Genetics, University of Wisconsin, Genetic Building
Junyu Lin: Laboratory of Genetics, University of Wisconsin, Genetic Building
John H.J. Petrini: Laboratory of Genetics, University of Wisconsin, Genetic Building
Michael B. Kastan: Department of Hematology–Oncology St. Jude Children's Research Hospital

Nature, 2000, vol. 404, issue 6778, 613-617

Abstract: Abstract The rare diseases ataxia-telangiectasia (AT), caused by mutations in the ATM gene, and Nijmegen breakage syndrome (NBS), with mutations in the p95/nbs1 gene, share a variety of phenotypic abnormalities such as chromosomal instability, radiation sensitivity and defects in cell-cycle checkpoints in response to ionizing radiation1,2,3,4. The ATM gene encodes a protein kinase that is activated by ionizing radiation or radiomimetic drugs5,6, whereas p95/nbs1 is part of a protein complex that is involved in responses to DNA double-strand breaks3,7. Here, because of the similarities between AT and NBS, we evaluated the functional interactions between ATM and p95/nbs1. Activation of the ATM kinase by ionizing radiation and induction of ATM-dependent responses in NBS cells indicated that p95/nbs1 may not be required for signalling to ATM after ionizing radiation. However, p95/nbs1 was phosphorylated on serine 343 in an ATM-dependent manner in vitro and in vivo after ionizing radiation. A p95/nbs1 construct mutated at the ATM phosphorylation site abrogated an S-phase checkpoint induced by ionizing radiation in normal cells and failed to compensate for this functional deficiency in NBS cells. These observations link ATM and p95/nbs1 in a common signalling pathway and provide an explanation for phenotypic similarities in these two diseases.

Date: 2000
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DOI: 10.1038/35007091

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