Identification of Small Molecules that Modulate Mutant p53 Condensation

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Mutations in the p53 tumor suppressor protein can lead to its destabilization, misfolding, and aggregation.
• Protein aggregation is increasingly recognized to involve intermediate condensate-like states.

Purpose of the Study:

• To investigate the formation of p53 mutant protein condensates in living cancer cells.
• To identify small molecules capable of modulating these p53 condensates.
• To differentiate the effects of these molecules on various p53 mutants.

Main Methods:

• Utilized fluorescently labeled p53 structural mutants in live cancer cell nuclei.
• Screened small molecule compounds for their ability to dissolve p53 condensates.
• Assessed compound effects on both structural and DNA-binding p53 mutants.

Main Results:

• Observed condensate-like states of structural mutant p53 within the nucleus of living cancer cells.
• Identified compounds that dissolve structural mutant p53 condensates.
• Demonstrated differential effects of compounds on p53 condensation based on mutation type, including inducing condensation in a DNA-binding mutant.

Conclusions:

• Structural mutant p53 proteins can form condensate-like structures in living cells.
• Small molecules can modulate these p53 condensates, offering potential therapeutic avenues.
• The identified compounds provide tools to study and potentially target mutant p53 behavior.