Abstract
Ataxia-telangiectasia is characterized by radiosensitivity, genome instability and predisposition to cancer1,2. Heterozygous carriers of ATM, the gene defective in ataxia-telangiectasia, have a higher than normal risk of developing breast and other cancers3,4,5,6. We demonstrate here that Atm 'knock-in' (Atm-ΔSRI) heterozygous mice harboring an in-frame deletion corresponding to the human 7636del9 mutation show an increased susceptibility to developing tumors. In contrast, no tumors are observed in Atm knockout (Atm+/−) heterozygous mice. In parallel, we report the appearance of tumors in 6 humans from 12 families who are heterozygous for the 7636del9 mutation. Expression of ATM cDNA containing the 7636del9 mutation had a dominant-negative effect in control cells, inhibiting radiation-induced ATM kinase activity in vivo and in vitro. This reduces the survival of these cells after radiation exposure and enhances the level of radiation-induced chromosomal aberrations. These results show for the first time that mouse carriers of a mutated Atm that are capable of expressing Atm have a higher risk of cancer. This finding provides further support for cancer predisposition in human ataxia-telangiectasia carriers.
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Acknowledgements
We thank the Australian National Health and Medical Research Council, the Ataxia-Telangiectasia Research Foundation (Los Angeles) and the Ataxia-Telangiectasia Children's Project (Florida) for support. Thanks to A. Farrell for technical support and T. Laing for typing the manuscript. P.J.M. acknowledges support from the NIH and the American Lebanese and Syrian Associated Charities (ALSAC) of St. Jude Children's Research Hospital. M.S. acknowledges support from the NIH.
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Spring, K., Ahangari, F., Scott, S. et al. Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer. Nat Genet 32, 185–190 (2002). https://doi.org/10.1038/ng958
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DOI: https://doi.org/10.1038/ng958
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