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

Hoseok Song, Monica Hollstein, Yang Xu

Research output: Contribution to journalArticle

256 Citations (Scopus)

Abstract

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. 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 p53mouse cells, the G2M 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.

Original languageEnglish
Pages (from-to)573-580
Number of pages8
JournalNature Cell Biology
Volume9
Issue number5
DOIs
Publication statusPublished - 2007 May
Externally publishedYes

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Ataxia Telangiectasia
Tumors
Neoplasms
DNA
DNA Damage
Carcinogenesis
Genetic Translocation
Double-Stranded DNA Breaks
Thymocytes
Tumor Suppressor Genes
Genes
Chemical activation
Alleles
Mutation

ASJC Scopus subject areas

  • Cell Biology

Cite this

p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM. / Song, Hoseok; Hollstein, Monica; Xu, Yang.

In: Nature Cell Biology, Vol. 9, No. 5, 05.2007, p. 573-580.

Research output: Contribution to journalArticle

Song, Hoseok ; Hollstein, Monica ; Xu, Yang. / p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM. In: Nature Cell Biology. 2007 ; Vol. 9, No. 5. pp. 573-580.
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