Investigate the Molecular Basis that Controls the Timing of Spindle Elongation

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DESCRIPTION (provided by applicant): Chromosome mis-segregation is a common cause of genetic disorders, including birth defects and cancer. Spindle elongation is essential for chromosome segregation and premature spindle elongation leads to abnormal chromosome segregation. Thus, the timing of spindle elongation must be rightly regulated. The objective of this application is to determine how cells ensure that spindle elongation occurs at the right time. The central hypothesis of the application is that, in budding yeast, the balance of mitotic CDK (cyclin dependent kinase) vs. S-phase CDK controls the timing of spindle elongation. S- phase CDK plays a negative role in spindle elongation by phosphorylating the S-phase CDK-specific substrates, whereas mitotic CDK promotes spindle elongation by indirectly stimulating the dephosphorylation of S-phase CDK substrates. The Cdc14 phosphatase is responsible for the dephosphorylation of S-phase CDK substrates and mitotic CDK allows this to happen by activating the FEAR (Cdc Fourteen Early Anaphase Release), a mitotic exit pathway that frees Cdc14 from the nucleolus during early anaphase. We further propose that S-phase CDK inhibits spindle elongation through the phosphorylation of Spc110, a component of the spindle pole body (SPB). We will take a comprehensive biochemical, genetic, and functional approach to study the timing control of spindle elongation in budding yeast. The objective of the application will be accomplished by pursuing three specific aims. 1) Test the hypothesis that S-phase and mitotic CDKs antagonistically regulate spindle elongation. 2) Test the hypothesis that mitotic CDK activates the FEAR pathway to counteract the negative effect of S-phase CDK on spindle elongation. 3) We hypothesize that S-phase CDK inhibits spindle elongation by phosphorylating Spc110, a component of the spindle pole body. The proposed work is innovative because it will reveal the molecular basis that controls the timing of spindle elongation. It is our expectation that the tightly regulated activities of mitotic and S-phase CDK during cell cycle ensure the correct timing of spindle elongation. Such outcomes will be significant because new knowledge will suggest new targets for preventing genetic disorders, such as cancer. Moreover, the support of this R15 proposal will enable the training of undergraduate students and expose them to biomedical research. PUBLIC HEALTH RELEVANCE: During mitosis, spindle elongation segregates duplicated chromosomes into two daughter cells. Premature spindle elongation leads to abnormal chromosome segregation, a characteristic of many cancer cells. This proposal aims to understand the molecular basis that controls the timing of spindle elongation. Therefore, this research will potentially uncover new targets for cancer diagnosis and treatment. Moreover, many undergraduate students will receive training in biomedical research by working on this project.