Regulating the p53 Tumor Suppressor Network at PML Biomolecular Condensates

SIMPLE SUMMARY: The cell nucleus is organized into different sub-nuclear compartments to control specific cellular processes, including PML nuclear bodies (NBs), also termed PML biomolecular condensates. PML-NBs form multi-protein complexes that are highly responsive to cellular stress, and regulate cell fate decisions in response to genome damage. By concentrating proteins that directly control the activity of the tumor suppressor p53, PML biocondensates guide the cellular response either towards induction of cell death or senescence through altering p53 modifications. In this review, we discuss the molecular mechanisms controlling PML condensate formation, and how they impact the regulation of p53 activity, and propose a list of promising candidate proteins that may contribute to the regulation of p53 at PML biomolecular condensates. ABSTRACT: By forming specific functional entities, nuclear biomolecular condensates play an important function in guiding biological processes. PML biomolecular condensates, also known as PML nuclear bodies (NBs), are macro-molecular sub-nuclear organelles involved in central biological processes, including anti-viral response and cell fate control upon genotoxic stress. PML condensate formation is stimulated upon cellular stress, and relies on protein–protein interactions establishing a PML protein meshwork capable of recruiting the tumor suppressor p53, along with numerous modifiers of p53, thus balancing p53 posttranslational modifications and activity. This stress-regulated process appears to be controlled by liquid–liquid phase separation (LLPS), which may facilitate regulated protein-unmixing of p53 and its regulators into PML nuclear condensates. In this review, we summarize and discuss the molecular mechanisms underlying PML nuclear condensate formation, and how these impact the biological function of p53 in driving the cell death and senescence responses. In addition, by using an in silico approach, we identify 299 proteins which share PML and p53 as binding partners, thus representing novel candidate proteins controlling p53 function and cell fate decision-making at the level of PML nuclear biocondensates.