p53-Dependent Repression: DREAM or Reality?

SIMPLE SUMMARY: The tumor suppressor p53 is a complex cell signaling hub encompassing multiple transcription programs and governs a vast repertoire of biological responses. However, despite several decades of research, how p53 selects one program over another is still elusive. Recent attempts have used meta-analyses of p53 ChIP-seq data to determine the core p53 transcriptional program, conserved across different models and stimuli. This review highlights the complexity of the multiple layers of p53 regulation and the context specificity of p53 target genes. More specifically, we discuss the controversy over the mechanisms of p53-dependent transcriptional repression and its potential role in the flexibility of p53 response. ABSTRACT: p53 is a major tumor suppressor that integrates diverse types of signaling in mammalian cells. In response to a broad range of intra- or extra-cellular stimuli, p53 controls the expression of multiple target genes and elicits a vast repertoire of biological responses. The exact code by which p53 integrates the various stresses and translates them into an appropriate transcriptional response is still obscure. p53 is tightly regulated at multiple levels, leading to a wide diversity in p53 complexes on its target promoters and providing adaptability to its transcriptional program. As p53-targeted therapies are making their way into clinics, we need to understand how to direct p53 towards the desired outcome (i.e., cell death, senescence or other) selectively in cancer cells without affecting normal tissues or the immune system. While the core p53 transcriptional program has been proposed, the mechanisms conferring a cell type- and stimuli-dependent transcriptional outcome by p53 require further investigations. The mechanism by which p53 localizes to repressed promoters and manages its co-repressor interactions is controversial and remains an important gap in our understanding of the p53 cistrome. We hope that our review of the recent literature will help to stimulate the appreciation and investigation of largely unexplored p53-mediated repression.