After almost two decades of research on direct repression by p53, I provide evidence that the transcription factor p53 solely acts as an activator of transcription. I evaluate the prominent models of transcriptional regulation by p53 based on a computational meta-analysis of genome-wide data. With this tool at hand, the major contradiction how p53 binding can result in activation of one target gene and repression of another is resolved. In contrast to most current models, solely genes activated by p53 are found to be enriched for p53 binding. Meta-analysis of large-scale data is unable to confirm reports on directly repressed p53 target genes and does not support models of direct repression. Consequently, as supported by experimental data, p53 is not a direct repressor of transcription, but solely activates its target genes. Moreover, models based on interference of p53 with activating transcription factors are also not supported by the meta-analysis. As an alternative to these models, the meta-analysis leads to the conclusion that p53 represses transcription indirectly by activation of the p53-p21- DREAM/RB pathway. Thus, results of the meta-analysis support only two models, namely activation by direct binding of p53 to target genes and repression through activating the p53-p21-DREAM/RB pathway.

After almost two decades of research on direct repression by p53, I provide evidence that the transcription factor p53 solely acts as an activator of transcription. I evaluate the prominent models of transcriptional regulation by p53 based on a computational meta-analysis of genome-wide data. With this tool at hand, the major contradiction how p53 binding can result in activation of one target gene and repression of another is resolved. In contrast to most current models, solely genes activated by p53 are found to be enriched for p53 binding. Meta-analysis of large-scale data is unable to confirm reports on directly repressed p53 target genes and does not support models of direct repression. Consequently, as supported by experimental data, p53 is not a direct repressor of transcription, but solely activates its target genes. Moreover, models based on interference of p53 with activating transcription factors are also not supported by the meta-analysis. As an alternative to these models, the meta-analysis leads to the conclusion that p53 represses transcription indirectly by activation of the p53-p21- DREAM/RB pathway. Thus, results of the meta-analysis support only two models, namely activation by direct binding of p53 to target genes and repression through activating the p53-p21-DREAM/RB pathway.