Abstract
A large number of signalling pathways converge on p53 to induce different cellular stress responses that aim to promote cell cycle arrest and repair or, if the damage is too severe, to induce irreversible senescence or apoptosis. The differentiation of p53 activity towards specific cellular outcomes is tightly regulated via a hierarchical order of post-translational modifications and regulated protein-protein interactions. The mechanisms governing these processes provide a model for how cells optimize the genetic information for maximal diversity. The p53 mRNA also plays a role in this process and this review aims to illustrate how protein and RNA interactions throughout the p53 mRNA in response to different signalling pathways control RNA stability, translation efficiency or alternative initiation of translation. We also describe how a p53 mRNA platform shows riboswitch-like features and controls the rate of p53 synthesis, protein stability and modifications of the nascent p53 protein. A single cancer-derived synonymous mutation disrupts the folding of this platform and prevents p53 activation following DNA damage. The role of the p53 mRNA as a target for signalling pathways illustrates how mRNA sequences have co-evolved with the function of the encoded protein and sheds new light on the information hidden within mRNAs.
Highlights
The p53 tumour suppressor protein is activated in response to various cellular stresses such as the DNA damage and the unfolded protein response (UPR) pathways
The p53 mRNA plays a role in regulating p53 activity and this review focuses on different ways by which the p53 mRNA helps differentiate p53-mediated response to signalling pathways
The role of synonymous mutations in controlling protein function is usually attributed to a switch between ‘fast’ and ‘slow’ codons that can affect translation elongation rate and how the protein is folded
Summary
The p53 tumour suppressor protein is activated in response to various cellular stresses such as the DNA damage and the unfolded protein response (UPR) pathways (for review see [1,2,3,4]). The appropriate cell biological response to the causing damage depends on cell type, intensity and duration of the stress and is the result of altered expression of some of p53’s several hundred target genes This includes genes associated with cell cycle progression through G1 or G2, metabolic pathways and cellular repair, or irreversible factors that induce apoptosis or cellular senescence (Figure 1). The differentiation of p53 activity includes post-translational modifications that regulate intrinsically disordered domains which provide interfaces for a large number of proteins [5,6]. In this way, p53 can select binding partners according to the signalling pathway. We describe how the p53 mRNA affects post-translational modifications and the stability of the nascent protein as well as the expression of p53 isoforms with unique functions
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