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.