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

The two sides of p53 The protein p53 is an important mediator of the DNA damage response and tumour suppression in vertebrates. In general, these two attributes are thought to be causally linked: p53 suppresses tumours by responding to DNA damage or genome abnormalities in tumour cells and triggering growth arrest or apoptosis. Now using a reversibly switchable endogenous p53 mouse model, Christophorou et al . show that the pathological p53-induced response to irradiation is irrelevant to p53-mediated suppression of tumours induced by that irradiation. Conversely, restoring p53 at later times avoids the pathological effects of irradiation but provides much of the tumour suppression. These data suggest that the DNA damage response and tumour suppression are unlinked activities of p53, each induced by distinct signals. A similar conclusion is drawn from a separate experiment, the absence of the tumour suppressor protein ARF was found to abolish the extra cancer-protective activity of an additional copy of p53 in mice. Again, this suggests that oncogenic signalling is critical for triggering protection by p53, whereas activation of p53 as a result of DNA damage has a lesser impact on the final development of tumours. In News and Views, Anton Berns looks at the implications of these findings for models of p53 activity. The tumour suppressor gene p53 is activated after DNA damage and helps eliminate damaged cells. But new evidence shows that during irradiation-induced tumourigenesis, p53 function in tumour suppression is not engaged by acute DNA damage, but later, in response to oncogene activation. 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 1 . 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 2 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 3 , that the p53-mediated pathological response to whole-body irr