Mutants defective in the normal cell cycle of yeast have been identified, some of which arrest with a nuclear division defect. Mutations in the CDC48 gene are conditionally defective in completing the segregation of mother and daughter nuclei, after normal migration of the nucleus into the bud-neck has occurred. Membranes isolated from mutant strains possess an in vitro defect in the fusion of nuclear membranes, as would be required for completion of nuclear fission. Biochemical evidence supports the idea that Cdc48 protein participates in membrane fusion events involving the nuclear envelope and endoplasmic reticulum. The proposed study will investigate the role of Cdc48p in nuclear envelope membrane fusion. Genetic and biochemical methodologies will be employed to investigate the mechanism of Cdc48p action during membrane fusion and to identify components that interact with Cdc48p. Subsequent analysis of Cdc48p interactors in biochemical assays will reveal if they act upstream of Cdc48p, such as cell cycle specific modulators, or if they are substrates of Cdc48p, such as proteins involved in the fusion of lipid bilayers. It is anticipated that many of these proteins will be needed for the fusion of endoplasmic reticulum membranes and thus mitosis.
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