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Dominant-negative TP53 mutations potentiated by the HSF1-regulated proteostasis network.

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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.

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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.