Abstract
The human genetic disorder ataxia-telangiectasia (AT) is characterized by immunodeficiency, progressive cerebellar ataxia, radiosensitivity, cell cycle checkpoint defects and cancer predisposition1. The gene mutated in this syndrome, ATM (for AT mutated), encodes a protein containing a phosphatidyl-inositol 3-kinase (PI-3 kinase)-like domain2,3. ATM also contains a proline-rich region4 and a leucine zipper2,5, both of which implicate this protein in signal transduction. The proline-rich region has been shown to bind to the SH3 domain of c-Abl, which facilitates its phosphorylation and activation by ATM (Refs 4,6). Previous results have demonstrated that AT cells are defective in the G1/S checkpoint activated after radiation damage and that this defect is attributable to a defective p53 signal transduction pathway7,8. We report here direct interaction between ATM and p53 involving two regions in ATM, one at the amino terminus and the other at the carboxy terminus, corresponding to the PI-3 kinase domain. Recombinant ATM protein phosphorylates p53 on serine 15 near the N terminus. Furthermore, ectopic expression of ATM in AT cells restores normal ionizing radiation (IR)-induced phosphorylation of p53, whereas expression of ATM antisense RNA in control cells abrogates the rapid IR-induced phosphorylation of p53 on serine 15. These results demonstrate that ATM can bind p53 directly and is responsible for its serine 15 phosphorylation, thereby contributing to the activation and stabilization of p53 during the IR-induced DNA damage response.
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Acknowledgements
The authors would like to thank J. Hancock, S. Goldstone, C. Harris, A. Robles and N. Zhang for helpful discussions and reagents, B. Garrone for photographic assistance, A. Farrell for technical assistance and A. Knight for typing the manuscript. Financial support was provided by the National Health and Medical Research Council of Australia, The Queensland Cancer Fund and A-T Childrens Project.
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Khanna., K., Keating, K., Kozlov, S. et al. ATM associates with and phosphorylates p53: mapping the region of interaction . Nat Genet 20, 398–400 (1998). https://doi.org/10.1038/3882
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DOI: https://doi.org/10.1038/3882
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