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Updated: Jun 7, 2025
14:57
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
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Dominant-negative TP53 mutations potentiated by the HSF1-regulated proteostasis network
Rebecca M Sebastian1, Jessica E Patrick1, Tiffani Hui2
1Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
Biorxiv : the Preprint Server for Biology
|November 18, 2024
Summary
Chronic activation of Heat Shock Factor 1 (HSF1) in cancer cells may promote oncogenic mutations by enhancing the fitness of destabilizing amino acid substitutions in proteins like p53. This suggests HSF1 inhibition could reduce drug resistance and metastasis.
Area of Science:
- Molecular Biology
- Biophysics
- Cancer Biology
Background:
- Protein stability and folding are influenced by mutations and the cellular proteostasis network.
- Heat Shock Factor 1 (HSF1) regulates proteostasis and is often chronically activated in cancer cells.
- This activation may facilitate the acquisition of oncogenic mutations.
Purpose of the Study:
- To experimentally investigate how chronic HSF1 activation impacts the mutational landscape of the p53 oncoprotein.
- To assess if HSF1 activation influences the fitness of p53 mutations under cytotoxic pressure.
Main Methods:
- Quantitative deep mutational scanning of p53.
- Assessment of p53 mutational pathways under nutlin-3 (MDM2 antagonist) treatment.
- Evaluation of HSF1 activation effects on mutation fitness.
Main Results:
- HSF1 activation broadly increased the fitness of dominant-negative p53 substitutions.
- This effect was pronounced for non-conservative, destabilizing substitutions in buried regions of the p53 DNA-binding domain.
- HSF1 activation preferentially supports cancer-associated, biophysically destabilizing mutations.
Conclusions:
- Chronic HSF1 activation significantly shapes the oncogenic mutational landscape.
- It favors the acquisition of destabilizing mutations that contribute to cancer.
- HSF1 inhibition may be a strategy to limit mutations driving chemotherapeutic resistance and metastasis.
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