CONDENSATES AND CANCER: THE PHASE BEHAVIOR OF P53

The tumor suppressor p53 is a metastable multidomain protein whose conformational plasticity is essential for cellular stress responses but may also favor pathological higher-order assemblies in cancer. Recent findings show that p53 aggregation can emerge through a phase-separation pathway, in which liquid condensates progressively mature into gel-like and amyloid-like states. The p53 DNA-binding domain undergoes condensation before aggregation, and cancer-associated mutations such as M237I and R249S accelerate this liquid-to-solid transition. These material-state changes are modulated by molecular crowding, temperature, conformational destabilization and polyanions, highlighting the nuclear environment as an active regulator of p53 phase behavior. In addition, mutant p53 can remodel the phase behavior of its paralogs p63 and p73, converting otherwise non-amyloid liquid droplets into heterotypic amyloid-like assemblies. Together, these studies position aberrant p53 condensation as a mechanistic link between structural instability, nuclear organization, prion-like conversion and oncogenic gain of function, offering new perspectives for therapeutic strategies aimed at pathological phase transitions.