Tumor suppressor p53: from engaging DNA to target gene regulation

Abstract

The p53 transcription factor confers its potent tumor suppressor functions primarily through the regulation of a large network of target genes. The recent explosion of next generation sequencing protocols has enabled the study of the p53 gene regulatory network (GRN) and underlying mechanisms at an unprecedented depth and scale, helping us to understand precisely how p53 controls gene regulation. Here, we discuss our current understanding of where and how p53 binds to DNA and chromatin, its pioneer-like role, and how this affects gene regulation. We provide an overview of the p53 GRN and the direct and indirect mechanisms through which p53 affects gene regulation. In particular, we focus on delineating the ubiquitous and cell type-specific network of regulatory elements that p53 engages; reviewing our understanding of how, where, and when p53 binds to DNA and the mechanisms through which these events regulate transcription. Finally, we discuss the evolution of the p53 GRN and how recent work has revealed remarkable differences between vertebrates, which are of particular importance to cancer researchers using mouse models.

Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress

“…In response to stress conditions, p53 transcriptionally regulates a plethora of target genes to suppress tumorigenesis (18, 19). Thereby, p53 influences diverse cellular processes, including apoptosis, cell cycle progression, and metabolism.…”

“…However, complex cross-talks between signaling pathways impede the identification of indirect regulations. Uncovering the molecular mechanisms through which p53 indirectly controls most p53-regulated genes, therefore, remains a longstanding challenge (19).…”

Dissecting the DNA binding landscape and gene regulatory network of p63 and p53

“…In contrast to the tumor suppressor p53 with its extensive set of target genes controlling the cell cycle and apoptosis ( Fischer, 2017 ; Sammons et al, 2020 ), its phylogenetically ancient sibling p63 (ΔNp63) governs epidermis development ( Mills et al, 1999 ; Yang et al, 1999 ) and is an oncogenic driver of squamous cell carcinoma (SCC) ( Cancer Genome Atlas Research Network et al, 2018 ; Gatti et al, 2019 ) that is overexpressed or amplified in SCCs, which depend on its expression ( Ramsey et al, 2013 ). Together with p73, p63, and p53 form the p53 transcription factor (TF) family that shares a highly conserved DNA binding domain (DBD) through which they bind to very similar DNA recognition motifs.…”

The guardian's choice: how p53 enables context‐specific decision‐making in individual cells

“…Beside PTM and oligomerization, other factors contribute to diversifying similar promoter binding dynamics to a specific target gene expression. For example, p53 interacts with other transcription factors as well as with several co-regulators that modify the surrounding chromatin structure to specifically induce defined cell fate programs (for detailed reviews, see [96,97]).…”