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

Area of Science:

• Molecular Biology
• Cancer Biology
• Genetics

Background:

• Protein stability and folding are crucial for cellular function and are influenced by proteostasis networks.
• Heat shock factor 1 (HSF1) is a key regulator of proteostasis, and its chronic upregulation is observed in cancer cells.
• Upregulated proteostasis may enable cancer cells to acquire and maintain oncogenic mutations.

Purpose of the Study:

• To investigate how HSF1 activation influences the mutational trajectories of p53.
• To understand how HSF1 affects p53's ability to escape cytotoxic pressure induced by nutlin-3, an MDM2 inhibitor.

Main Methods:

• Assessing the impact of HSF1 activation on p53 mutational escape.
• Analyzing the fitness of dominant-negative p53 substitutions under HSF1 activation.
• Examining specific amino acid changes within the p53 DNA-binding domain.

Main Results:

• HSF1 activation significantly increases the fitness of dominant-negative p53 substitutions.
• This effect is particularly pronounced for non-conservative, biophysically unfavorable mutations in buried regions of the p53 DNA-binding domain.
• HSF1 activation preferentially supports the emergence and persistence of disruptive, cancer-associated p53 mutations.

Conclusions:

• HSF1 activation reshapes the oncogenic mutational landscape.
• It provides a selective advantage for biophysically disruptive p53 substitutions.
• This links proteostasis network activity directly to cancer evolution and the maintenance of oncogenic mutations.