(a) Transactivation domain 1 (TAD1) and robust transactivation of classical p53 target genes are required for responses to acute DNA damage, including apoptosis and cell cycle arrest. A p53 TAD1 mutant, p5325,26, is unable to efficiently activate expression of canonical p53 target genes, including p21, Noxa, Perp, and Puma. p5325,26 is also unable to induce apoptosis or cell cycle arrest in response to acute DNA damage. Transactivation by either TAD1 or TAD2 allows p53 responses to oncogene activation. p5325,26 can activate expression of only a limited number of mostly novel target genes, but can promote tumor suppression in a number of mouse models. The tumor suppressor capability of p5325,26 can be explained by its ability to robustly activate a limited set of novel direct p53 target genes (Sidt2, Phlda3, Abhd4, etc.). The capacity of p5325,26 to promote very low level activation of various classical p53 target genes may also contribute to tumor suppression. The “?” denotes additional, still-unknown genes critical for responses to acute DNA damage and oncogene activation. (b) Comparison of gene expression profiles of p53 wild-type and p53-null HrasV12-MEFs results in more than 1000 differentially expressed genes. To enrich for genes with specific roles in tumor suppression, we leveraged gene expression profiling data generated with the p5325,26 mutant, which activates only a small subset of p53 target genes, yet is a potent tumor suppressor. Using transcriptomics analysis of HrasV12-MEFs, we identified genes induced at least 2 fold and within 1.5 standard deviations by p53wt, p5325,26, and p5353,54, which all have tumor suppressor activity, relative to p5325,26,53,54 or p53-null samples, which lack tumor suppressor activity. This list of 130 genes was then filtered for those commonly downregulated in human and mouse tumors, according to the EBI’s Gene Atlas database. A group of 14 candidate genes with likely roles in p53-mediated tumor suppression was defined by this analysis.