Subsequently, with the evolution of longerliving organisms, p53 is thought to have acquired the ability to respond to oncogenic signals, promoting apoptosis or senescence–a permanent cell-cycle-arrest response–as a safeguard against neoplasia. Thus, in cells exposed to potent stress signals, p53 drives irreversible programs of apoptosis or senescence to cull irreparably damaged or malignant cells, for the ultimate benefit of the organism (Vousden and Prives, 2009). Alternatively, under conditions of low-level stress, p53 elicits protective, pro-survival responses, such as temporary cell-cycle arrest, DNA repair and antioxidant protein production, to maintain genome integrity and viability in cells that sustain limited, reparable damage. These various responses rely on the ability of p53 to function as a transcriptional activator of a panoply of target genes, although transactivation-independent activities ascribed to p53 can also contribute to p53-mediated responses, as highlighted below. p53 has protein domains typical of transcriptional activators

Similarly to other transcription factors, p53 has a modular protein domain structure (Joerger and Fersht, 2007; Vousden and Prives, 2009). The N-terminus of p53 comprises two transcriptional activation domains (TADs), TAD1 and TAD2, which span amino acid residues 1-40 and 40-60, respectively. These domains can independently enhance transcription of p53 target genes by recruiting histone-modifying enzymes, components of the basal transcriptional machinery and coactivator complexes, such as STAGA and Mediator (Gamper and Roeder, 2008; Joerger and Fersht, 2007). C-terminal to the transactivation domains, between residues 60-95, lies the proline-rich domain (PRD), which was originally proposed to participate in protein-protein interactions on the basis of the presence of PxxP motifs that resemble Src homology 3 (SH3)-domainbinding regions (Toledo et al., 2006; Toledo et al., 2007). However, a structural function might be the main role of this domain because knock-in mice carrying proline-to-alanine point mutations in the putative protein-protein interaction sites of this domain appear normal, whereas complete domain deletion disrupts p53 tumor-suppressor function. The central core of p53, which spans residues 100-300, comprises the DNA-binding domain that is responsible for sequence-specific binding of the protein to p53 response elements in DNA. Most cancerassociated p53 mutations are missense mutations in this domain and incapacitate DNA binding, illuminating the key importance of DNA binding for p53-mediated tumor