Phase separation of Ki-67 during mitotic exit

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Compartmentalization into functional units is a key principle of cellular life. In addition to membrane-bound organelles, eukaryotic cells utilize membrane-less biomolecular condensates to locally concentrate proteins and nucleic acids. While we are beginning to understand the principles that underlie membrane-less condensate assembly and disassembly, we know very little about the biological processes that take place at the surface of such condensates. The surface of the largest membrane-less cellular assembly, the mitotic chromosome, is covered by the intrinsically disordered protein Ki-67. Our previous studies have revealed that Ki-67 has dual functionality. In early mitosis, Ki-67 functions as a surfactant to prevent chromosomes from collapsing into a single chromatin mass, whereas it actively promotes chromosome clustering during exit from mitosis. How Ki-67 switches between these two opposing activities – chromosome dispersal and chromosome clustering – has remained unknown. Here, I outline an interdisciplinary research program that combines cell biological and proteomics approaches with novel in-vitro reconstitution systems to gain insight into the physicochemical properties that underlie the switch of Ki-67 from chromosome repellent to chromosome attractant. The results from this project have the potential to not only reveal new insights into the biophysical nature of mitotic chromosomes but have the potential to reveal new general principles of cellular organization that occur on the surface of membrane-less assemblies.