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

      Nature

      Tumor Suppressor Proteins, Ataxia Telangiectasia, metabolism, Tumor Suppressor Protein p53, Transfection, Signal Transduction, Serine, S Phase, genetics, Recombinant Fusion Proteins, radiation effects, Protein-Serine-Threonine Kinases, Phosphorylation, Phosphatidylinositol 3-Kinases, Nuclear Proteins, Mutagenesis, Humans, Enzyme Activation, DNA-Binding Proteins, biosynthesis, DNA, Cell Line, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins

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          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 radiation. The ATM gene encodes a protein kinase that is activated by ionizing radiation or radiomimetic drugs, whereas p95/nbs1 is part of a protein complex that is involved in responses to DNA double-strand breaks. 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.

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          Journal
          10766245
          10.1038/35007091

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