Tune p53 transactivation and tumor suppression activity by modulating its liquid-liquid phase separation propensity

p53, essential in cancer defence, is involved in transcriptional and DNA repair condensates. However, whether condensation can be driven by endogenous p53 and the functional significance of condensates in p53’s working and regulatory mechanisms were unknown. We show that endogenous p53 forms nanoscale condensates, co-localizing with different co-factors, enabling distinct functions within segregated compartments in cells. Antagonists disperse these condensates, whereas activators enhance coalescence and alter p53 dynamics within these structures. Notably, we reveal a dual role for p53: it maintains tumor suppression and, paradoxically, boosts expression of neuron-related genes, which in certain contexts, can promote cancer cell growth. We developed liquid-liquid phase separation- enhanced p53 variants that amplify selected target gene transactivation and suppress oncogenic gene upregulation, curtailing proliferation of cancer cells resistant to wild-type p53. These findings reveal a critical role of liquid-liquid phase separation in p53 functional regulation, offering subtle control over its transcriptional landscape, particularly with respect to specific genes intersecting neuronal signalling and cancer pathways..