p53 plays a central role in defending the genomic integrity of our cells. In response to genotoxic stress, this tumour suppressor orchestrates the expression of hundreds of target genes, which induce a variety of cellular outcomes ranging from damage repair to induction of apoptosis. In this review, we examine how the p53 response is regulated on several levels in individual cells to allow precise and context-specific fate decisions. We discuss that the p53 response is not only controlled by its canonical regulators but also controlled by interconnected signalling pathways that influence the dynamics of p53 accumulation upon damage and modulate its transcriptional activity at target gene promoters. Additionally, we consider how the p53 response is diversified through a variety of mechanisms at the promoter level and beyond to induce context-specific outcomes in individual cells. These layers of regulation allow p53 to react in a stimulus-specific manner and fine-tune its signalling according to the individual needs of a given cell, enabling it to take the right decision on survival or death.
Keywords: DNA damage response; apoptosis; cell cycle arrest; p53; post-transcriptional modifications; protein dynamics; signalling crosstalk; single cell analysis; stochastic gene expression.
© 2021 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.