Temporal-spatial control of mitotic regulators by polySUMOylation

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Abstract SUMOylation is an essential post-translational modification that adds small ubiquitin-like modifiers (SUMO) to protein lysine residues. SUMOylation regulates many cellular functions, including cell proliferation, DNA repair, and stress response. Deregulation of SUMOylation contributes to genome instability and cancer development. Attachment of single SUMO to proteins often creates scaffolds to nucleate macromolecular interactions. On the other hand, attachment of chains of SUMO (polySUMOylation) often triggers protein ubiquitination and extraction from a macromolecular complex. Recent works demonstrate polySUMO-dependent relocation of damaged DNA, which facilitates damage repair. However, the function of protein polySUMOylation and its regulation during cell cycle remain poorly defined. Our long-term goal is to uncover the molecular mechanisms that control genome stability to provide fundamental knowledge that will help develop treatment strategies for diseases resulting from genome instability, such as cancer. The objective of this project is to investigate how polySUMOylation controls the relocation of two key mitotic regulators during the cell cycle: the RENT (regulator of nucleolar silencing and telophase) critical for mitotic exit, and the CPC (chromosomal passenger complex), essential for chromosome bipolar attachment. We recently found that polySUMOylation induction in yeast cells triggers relocation of these two critical mitotic regulators. Our preliminary data support the central hypothesis that polySUMOylation promotes relocation of some key mitotic regulators for successful anaphase initiation, and activation of polo-like kinase triggers polySUMOylation by phosphorylating a deSUMOylase. Our objective will be attained via the following specific aims: 1) Elucidate the mechanism of polySUMOylation-triggered nucleolar protein delocalization that promotes mitotic exit. 2) Determine how polySUMOylation of CPC subunits promotes CPC translocation. 3) Investigate the temporal control mechanism for polySUMOylation during the cell cycle. To test our hypothesis and achieve our aims, we will combine budding yeast genetics, cell biology, and biochemistry. Successful completion of this research will provide a comprehensive understanding of how polySUMOylation controls subcellular localization of protein complexes in the context of cell cycle. Given the exceptional conservation of both the SUMO system and the cell cycle machinery, principles proved in budding yeast are highly likely to translate to human and other eukaryotes. The results will have an important positive impact on the cell biology field because they will uncover new mechanisms critical for genome stability and unveil new targets for cancer diagnosis and therapy.