Letter abstract
Nature Cell Biology 9, 573 - 580 (2007)
Published online: 8 April 2007 | doi:10.1038/ncb1571
p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM
Hoseok Song1, Monica Hollstein2,3 & Yang Xu1
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.
- Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093–0322, USA.
- Department of Genetic Alterations in Carcinogenesis, German Cancer Research Center, Heidelberg, Germany.
- Current address: Light Laboratories, University of Leeds, Faculty of Medicine and Health, Clarendon Way, Leeds LS2 9JT, UK.
Correspondence to: Yang Xu1 e-mail: yangxu@ucsd.edu
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