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Published on: June 12, 2018
The p53 mRNA: an integral part of the cellular stress response
Lucia Haronikova1, Vanesa Olivares-Illana2, Lixiao Wang3
1RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53 Brno, Czech Republic.
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.
Insights
The p53 mRNA acts as a regulatory platform, controlling protein synthesis and stability. Specific mutations in this mRNA can block p53 activation, impacting cellular stress responses.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Signaling pathways converge on p53 to manage cellular stress responses, including cell cycle arrest, senescence, and apoptosis.
- p53 activity is regulated by post-translational modifications and protein-protein interactions, optimizing genetic information for cellular diversity.
Purpose of the Study:
- To illustrate how protein and RNA interactions involving p53 mRNA regulate RNA stability, translation efficiency, and alternative translation initiation.
- To describe the riboswitch-like features of p53 mRNA and its control over p53 protein synthesis, stability, and nascent protein modifications.
Main Methods:
- Review of existing literature on p53 signaling pathways, post-translational modifications, and mRNA regulation.
- Analysis of protein-RNA interactions and their impact on p53 mRNA function.
- Examination of riboswitch-like features within the p53 mRNA structure.
Main Results:
- p53 mRNA interacts with proteins and signaling pathways to control RNA stability and translation.
- The p53 mRNA functions as a platform with riboswitch-like properties, regulating p53 synthesis and protein modifications.
- A synonymous mutation in cancer disrupts p53 mRNA folding, inhibiting p53 activation after DNA damage.
Conclusions:
- p53 mRNA sequences have co-evolved with p53 protein function, acting as a direct target for signaling pathways.
- The regulatory role of p53 mRNA reveals hidden information within mRNA sequences, impacting cellular responses to stress and DNA damage.
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