Nature cell biologyApr 10, 2007

Cancer-related p53 mutations may cause genetic instability by blocking the DNA damage response protein ATM

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Updated Apr 5, 2026

Abstract

p53(R248W) mice develop cancers more rapidly than p53(-/-) mice.

p53 mutations lead to the loss of tumor-suppressor functions in mice.
p53(R248W) and p53(R273H) mutations are associated with novel oncogenic activities.
Genetic instability, indicated by interchromosomal translocations, is present in p53-mutant pre-tumor thymocytes.
The G(2)-M checkpoint is impaired in p53-mutant cells following DNA damage, unlike in p53(-/-) cells.
Mutant p53 proteins may disrupt DNA damage-response pathways by interacting with the nuclease Mre11.

Simplified

Tp53 is the most commonly mutated tumour-suppressor gene in human cancers. In addition to the loss of tumour-suppression function, some missense mutants gain novel oncogenic activities. 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. p53(R248W) 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 G(2)-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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Cancer-related p53 mutations may cause genetic instability by blocking the DNA damage response protein ATM

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