The chameleonic behavior of p53 in health and disease: Phase separation and aggregation of mutant p53 as an emerging target in cancer
Jerson L. Silva
Institute of Medical Biochemistry Leopoldo de Meis, National Institute of Science and Technology for Structural Biology and Bioimaging, National Center of Nuclear Magnetic Resonance Jiri Jonas, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
Biomolecular condensates are membraneless structures originated from liquid-liquid phase separation. In addition to the physiological roles, condensates can undergo a solid-phase transition, generating amyloid-like structures involved in degenerative diseases and cancer. We will present recent studies on the formation of biomolecular condensates and aggregates in proteins involved in cancer, with a special focus on the tumor suppressor protein p53. In 1972 the Weber statement, “The multiplicity of interactions and the variety of effects that follow from them show that multimer proteins are unlikely to be limited to a minimal number of allowed conformations”, first addressed the dynamic nature of proteins. This idea serves as a foundation for understanding why several macromolecules, such as p53, exhibit the properties of a molecular chameleon. More than half of the malignant tumors harbor mutations in the TP53 gene and will kill hundreds of million people if new therapies are not developed soon enough. We have explored the findings that mutant p53 not only undergoes misfolding, but also forms biomolecular condensates and aggregates comparable to amyloids formed by other proteins, thereby playing a crucial role in cancer development through loss of function (LoF), negative dominance (ND) and gain of function (GoF) mechanisms. Strikingly, as in the case of toxic amyloids in neurodegenerative diseases, the molecular mechanisms responsible for the GoF of mutant p53 are not yet completely understood. However, we already know that different cofactors, such as nucleic acids and glycosaminoglycans, are at the crossroads between these two classes of diseases. Importantly, molecules that inhibit mutant p53 aggregation reduce tumor proliferation and migration. Thus, aberrant phase separation and aggregation of mutant p53 have become important therapeutic targets against cancer. (Supported by funds from CNPq, FAPERJ, CAPES and FINEP).