The pathological response to DNA damage does not contribute to p53-mediated tumour suppression

Maria Christophorou, I Ringshausen, A J Finch, L Brown Swigart, G I Evan

Research output: Contribution to journalArticlepeer-review

Abstract

The p53 protein has a highly evolutionarily conserved role in metazoans as 'guardian of the genome', mediating cell-cycle arrest and apoptosis in response to genotoxic injury. In large, long-lived animals with substantial somatic regenerative capacity, such as vertebrates, p53 is an important tumour suppressor--an attribute thought to stem directly from its induction of death or arrest in mutant cells with damaged or unstable genomes. Chemotherapy and radiation exposure both induce widespread p53-dependent DNA damage. This triggers potentially lethal pathologies that are generally deemed an unfortunate but unavoidable consequence of the role p53 has in tumour suppression. Here we show, using a mouse model in which p53 status can be reversibly switched in vivo between functional and inactive states, that the p53-mediated pathological response to whole-body irradiation, a prototypical genotoxic carcinogen, is irrelevant for suppression of radiation-induced lymphoma. In contrast, delaying the restoration of p53 function until the acute radiation response has subsided abrogates all of the radiation-induced pathology yet preserves much of the protection from lymphoma. Such protection is absolutely dependent on p19(ARF)--a tumour suppressor induced not by DNA damage, but by oncogenic disruption of the cell cycle.
Original languageEnglish
Pages (from-to)214-7
Number of pages4
JournalNature
Volume443
Issue number7108
DOIs
Publication statusPublished - 14 Sep 2006

Keywords

  • Cyclin-Dependent Kinase Inhibitor p16
  • Animals
  • Tumor Suppressor Protein p53
  • DNA Damage
  • Tumor Suppressor Protein p14ARF
  • Neoplasms, Radiation-Induced
  • Mice
  • Lymphoma

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