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

Nat Cell Biol. 2007 May;9(5):573-80. doi: 10.1038/ncb1571. Epub 2007 Apr 8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism
  • Acid Anhydride Hydrolases
  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Cells, Cultured
  • DNA Breaks, Double-Stranded / radiation effects
  • DNA Repair Enzymes / metabolism
  • DNA-Binding Proteins / metabolism*
  • Fibroblasts / metabolism
  • Fibroblasts / radiation effects
  • Gene Expression Regulation, Neoplastic*
  • Genomic Instability*
  • Histones / metabolism
  • Humans
  • MRE11 Homologue Protein
  • Mice
  • Mice, Transgenic
  • Mutation*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Nuclear Proteins / metabolism
  • Phosphorylation
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Signal Transduction / genetics*
  • Thymus Gland / cytology
  • Thymus Gland / metabolism
  • Transcription, Genetic
  • Translocation, Genetic
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / metabolism*
  • Ultraviolet Rays


  • ATP-Binding Cassette Transporters
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • H2AX protein, mouse
  • Histones
  • Mre11a protein, mouse
  • Nijmegen breakage syndrome 1 protein, mouse
  • Nuclear Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein Serine-Threonine Kinases
  • MRE11 Homologue Protein
  • Acid Anhydride Hydrolases
  • Rad50 protein, mouse
  • DNA Repair Enzymes