The role of DNA damage responses in p53 biology

The tumour suppressor p53 is a central player in cellular DNA damage responses. P53 is upregulated and activated by genotoxic stress and induces a transcriptional programme with effectors promoting apoptosis, cell cycle arrest, senescence and DNA repair. For the best part of the last three decades, these DNA damage-related programmes triggered by p53 were unequivocally regarded as the major if not sole mechanism by which p53 exerts its tumour suppressor function. However, this interpretation has been challenged by a number of recent in vivo studies, demonstrating that mice which are defective in inducing p53-dependent apoptosis, cell cycle arrest and senescence suppress thymic lymphoma as well as wild-type p53 expressing animals. Consequently, the importance of DNA damage responses for p53-mediated tumour suppression has been questioned. In this review, I summarize current knowledge on p53-controlled DNA damage responses and argue that these activities, while their role has certainly changed, remain an important feature of p53 biology with relevance for cancer therapy and tumour suppression.