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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
TP53: the unluckiest of genes?
Andreas C Joerger1,2, Thorsten Stiewe3,4, Thierry Soussi5,6
1Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt am Main, Germany. joerger@pharmchem.uni-frankfurt.de.
Abstract:
The transcription factor p53 plays a key role in the cellular defense against cancer development. It is inactivated in virtually every tumor, and in every second tumor this inactivation is due to a mutation in the TP53 gene. In this perspective, we show that this diverse mutational spectrum is unique among all other cancer-associated proteins and discuss what drives the selection of TP53 mutations in cancer. We highlight that several factors conspire to make the p53 protein particularly vulnerable to inactivation by the mutations that constantly plague our genome. It appears that the TP53 gene has emerged as a victim of its own evolutionary past that shaped its structure and function towards a pluripotent tumor suppressor, but came with an increased structural fragility of its DNA-binding domain. TP53 loss of function - with associated dominant-negative effects - is the main mechanism that will impair TP53 tumor suppressive function, regardless of whether a neomorphic phenotype is associated with some of these variants.
Insights
The TP53 gene, crucial for cancer defense, exhibits a unique mutation spectrum. Its evolutionary history contributes to p53 protein structural fragility, driving TP53 mutations in cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The p53 protein is a critical tumor suppressor involved in cellular defense against cancer.
- TP53 gene mutations are found in approximately half of all human tumors, highlighting their significance in cancer development.
Purpose of the Study:
- To investigate the unique mutational spectrum of the TP53 gene in cancer.
- To understand the driving factors behind the selection of TP53 mutations.
- To explore how the evolutionary past of TP53 influences its vulnerability to mutations.
Main Methods:
- This perspective discusses existing literature and data on TP53 mutations and p53 protein function.
- Analysis of the TP53 mutational landscape in various cancer types.
- Review of evolutionary pressures and structural properties of the p53 protein.
Main Results:
- The TP53 gene displays a mutation spectrum distinct from other cancer-associated genes.
- Multiple factors contribute to the vulnerability of the p53 protein to inactivating mutations.
- The evolutionary trajectory of TP53 has resulted in a structurally fragile DNA-binding domain.
Conclusions:
- TP53 mutations are selected in cancer due to a combination of factors, including the protein's inherent structural fragility.
- Loss of function, often with dominant-negative effects, is the primary mechanism by which TP53 mutations impair tumor suppression.
- Understanding these mechanisms is crucial for developing targeted cancer therapies.
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