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Genome Stability: Coordination of chromosome segregation with cell division


Mitosis is an intricately coordinated set of events that ensures the accurate inheritance of genetic information from one cell generation to the next. The genome, packed into chromosomes, is distributed between two daughter cells during anaphase. After completion of anaphase cells divide, i.e. undergo cytokinesis.

It is poorly understood what regulates the timing of cytokinesis such that it only happens after anaphase is complete. How eukaryotes, including human, inherit their nuclear genome is a fundamental question in biology. It also has direct clinical implications as chromosome missegregation is a leading cause for miscarriages and birth defects, and is tightly linked to malignant tumour progression. This project has broad relevance to both the understanding of a fundamental biological process as well as human disease.

We want to address how anaphase is coordinated with cytokinesis using budding yeast as the model system. Recent advances in the Dr. Uhlmann's laboratory have shown that the protease "separase" triggers sister chromatid separation at anaphase onset and at the same time activates a phosphatase called "Cdc14". The Cdc14 phosphatase in turn is a key molecule thought to initiate cytokinesis. This dual role of separase is therefore critical t o the coordination of anaphase with cytokinesis.

Two principal questions arise from this finding that will be addressed in this proposal: - How does one protein, separase, at the same time fulfil two roles, separation of sister chromatids as well as activation of Cdc14 phosphatase?
- Given that Cdc14 phosphatase is activated simultaneously with anaphase onset, how is down-regulation of Cdk activity regulated to ensure completion of chromosome segregation before cytokinesis?

To address these questions will include identification of separase interacting proteins responsible for Cdc14 activation, as well as biochemical techniques to define the pathway that controls its timing.

Call for proposal

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