The equal distribution of chromosomes into daughter cells depends upon the accurate assembly of the mitotic spindle at cell division. The inappropriate segregation of chromosomes leads to aneuploidy, which can result in cell death or carcinogenesis. Proteins that control the cytoskeleton, including those that regulate microtubule dynamics and spindle assembly, can be oncogenic when altered. Our goal is to understand the function of the centrosome in cytoskeletal organization and other cellular processes. To achieve this, we must understand the roles of proteins that function at the centrosome. Our main focus is on Centrosomin (Cnn), a major core component of centrosomes in Drosophila. Cnn is a phosphoprotein with three putative leucine zippers, extensive coiled-coil domains, and two novel motifs that are highly conserved across species. Cnn is required to assemble functional centrosomes at mitosis. In somatic cells that lack Cnn, mitosis occurs efficiently, but by an alternate, anastral pathway. We hypothesize that the anastral pathway for mitosis may be a vestige of an evolutionary precursor to the current centrosomal mode of mitosis that is found in most animal cells. The purpose of this project is to understand the functions of Cnn and centrosomes in cell division, and to define the anastral pathway for mitosis.
Three specific aims are designed to accomplish these goals.
The first aim i s to dissect the functional domains in Cnn protein using in vivo functional and rescue assays, to examine potential human homologs by rescue of Cnn in Drosophila, and to examine the role of phosphorylation in Cnn function.
Our second aim i s to identify Cnn protein partners using genetic and biochemical approaches, then assay their localization in the cell, their role in centrosome function, and their role in centrosomal localization of Cnn.
Our third aim i s to define the anastral meiosis-like pathway that is induced in cells that lack Cnn. The mechanisms for spindle assembly and chromosome segregation at mitosis in cells that lack Cnn (and have dysfunctional centrosomes) will be investigated.
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