Mitotic regulation is fundamentally important to all eukaryotic life and has medical significance as mitotic defects can lead to aneuploidy and cancer. Mitosis is regulated by a complex interplay of conserved protein kinases but there is a limited understanding of the pertinent kinase substrates and the mechanistic consequences of their phosphorylation. For example, it is unknown how mitotic kinases regulate the stepwise disassembly and reassembly of the nuclear pore complex (NPC) during open mitosis. My laboratory has shown that during the closed mitosis of the model filamentous fungus Aspergillus nidulans, the NPC is partially disassembled with at least 12 NPC proteins (Nups) reversibly dispersing from a core NPC structure. A. nidulans therefore represents a unique and powerful model genetic system in which the NPC is regulated during mitosis in a manner displaying many similarities to human mitotic NPC regulation. Interestingly, A. nidulans An-Nup2 exclusively re-locates to mitotic chromosomes, suggesting a novel mitotic role for this Nup. This proposal aims to: i) Define in detail the reversible changes in the composition of the NPC during mitosis, ii) Characterize how NPC architecture changes when it is disassembled and assembled and relate this to NPC composition and function, iii) Establish how mitotic specific phosphorylation regulates the structure and function of the NPC, and iv) Determine how the localization of An-Nup2 to chromatin helps coordinate NPC disassembly/reassembly with mitotic progression. These studies will help define how the NPC is regulated by kinases during mitosis and how the mitotic regulation of Nups is integrated with mitotic progression. ? ?
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