In broad terms our research is directed at elucidating the control mechanisms for cell division. We use living cells and egg extracts to provide information that cannot be obtained from conventional biochemical and molecular approaches. 1. We developed the first Xenopus egg extract that supports multiple rounds of centrosome reproduction. We will finish our characterization of this experimental system and then use it to further investigate the mechanisms that control centrosome reproduction and coordinate it with nuclear events in the cell cycle, with an emphasis on the role of cyclin dependent kinase 2-cyclin E (Cdk2-E) in the regulation of centrosome reproduction. 2. We will characterize the activities of Cdks complexed with cyclins A and E when sea urchin zygotes are arrested in G1 and S phases and correlate these activities with the different abilities of centrosomes to repeatedly reproduce in these cell cycle phases. 3. We will use mammalian somatic cells to test whether the initiation of centriole duplication can occur during G1, without cell cycle progression into S phase. This should provide new insight into the centriole cycle and its cell cycle regulation. 4. We will test the hypothesis that the spindle, not the cytoplasm, provides the competency for the cell to execute the metaphase-anaphase transition. 5. We will use vertebrate somatic cells to study the regulation of chromatid cohesion at the metaphase-anaphase transition. Health relevance: We study the control of centrosome reproduction because a wide variety of human tumors have an abnormally high number of centrosomes; this can directly lead to aneuploidy and genomic instability through the formation of multipolar spindles at mitosis. We study the regulation of chromatid cohesion, because failure of the sister chromatid arms to completely release at anaphase onset directly leads to chromosome breakage or chromosome non-disjunction, either of which leads to genetic damage that can promote neoplastic transformation.
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