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p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM

Nature Cell Biology volume 9, pages 573–580 (2007)Cite this article

Abstract

Tp53 is the most commonly mutated tumour-suppressor gene in human cancers1. In addition to the loss of tumour-suppression function, some missense mutants gain novel oncogenic activities2. To elucidate the nature of the gain of function, we introduced the most common p53 cancer mutations (R248W and R273H) independently into the humanized p53 knock-in (HUPKI) allele in mice. Tumour-suppressor functions of p53 are abolished in p53-mutant mice. Several lines of evidence further indicate gain-of-function of p53 mutants in promoting tumorigenesis. p53R248W mice rapidly succumb to certain types of cancers not commonly observed in p53−/− mice. Interchromosomal translocations, a type of genetic instability rarely observed in p53−/− cells, are readily detectable in p53-mutant pre-tumor thymocytes. Although normal in p53−/− mouse cells, the G2–M checkpoint is impaired in p53-mutant cells after DNA damage. These acquired oncogenic properties of mutant p53 could be explained by the findings that these p53 mutants interact with the nuclease Mre11 and suppress the binding of the Mre11–Rad50–NBS1 (MRN) complex to DNA double-stranded breaks (DSBs), leading to impaired Ataxia-telangiectasia mutated (ATM) activation. Therefore, p53 gain-of-function mutants promote tumorigenesis by a novel mechanism involving active disruption of critical DNA damage-response pathways.

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Figure 1: p53 stability and activity in p53hki and p53R248W MEFs.
Figure 2: Tumorigenesis in p53R248W mice.
Figure 3: Inter-chromosomal rearrangement involving TCRγ–TCRβ loci in pre-tumour mouse thymocytes.
Figure 4: Impaired cell-cycle G2–M checkpoint and ATM activation in p53R248W and p53R273H cells after irradiation.
Figure 5: Impaired recruitment of the MRN complex to sites of DNA DSB damage.

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Acknowledgements

We thank J. Earle, L. Feng, J. Kang and Z. Wu for technical support, J. Petrini for anti-mouse Mre11 antibodies and R. Brachmann for critically reading the manuscript. This work was supported by a Department of Defense Prostate Cancer Research Program (W81XWH-05-1-0006) prostate cancer research grant and a National Institute of Health (NIH) grant (CA77563) to Y.X.

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  1. Monica Hollstein

    Present address: Current address: Light Laboratories, University of Leeds, Faculty of Medicine and Health, Clarendon Way, Leeds LS2 9JT, UK.,

Authors and Affiliations

  1. Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093–0322, CA, USA

    Hoseok Song & Yang Xu

  2. Department of Genetic Alterations in Carcinogenesis, German Cancer Research Center, Heidelberg, Germany

    Monica Hollstein

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Correspondence to Yang Xu.

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Song, H., Hollstein, M. & Xu, Y. p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM. Nat Cell Biol 9, 573–580 (2007). https://doi.org/10.1038/ncb1571

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