Control of cell division by ubiquitin-mediated protein degradation.

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The cell division cycle is driven by oscillations in the levels of regulatory proteins such as cyclins, inhibitors of cyclin-dependent protein kinases and inhibitors of anaphase initiation. The programmed degradation of various cell cycle regulatory proteins is carried out by the ubiquitin system, which targets proteins for degradation by ligation to ubiquitin. The timely ligation to ubiquitin of such regulatory proteins is carried out by specific ubiquitin-protein ligases. Of these, I am focusing recently on the mode of action and regulation of the Anaphase-Promoting Complex/Cyclosome (APC/C), a multi-subunit ubiquitin ligase complex that is essential for exit from mitosis and for preventing premature transition from G1 to S phase of the cell cycle. APC/C is also the target of the mitotic checkpoint (or spindle assembly checkpoint) system, a surveillance mechanism that ensures the fidelity of chromosome segregation in mitosis by delaying anaphase initiation until all chromosomes are correctly attached to the mitotic spindle. When the mitotic checkpoint is active, it generates inhibitors of APC/C that prevent its action to target for degradation anaphase inhibitors such as securin and cyclin B. An important inhibitor of APC/C is the Mitotic Checkpoint Complex (MCC), which assembles when the checkpoint is turned on and disassembles when the checkpoint signal is extinguished. We are studying the molecular mechanisms of the assembly and disassembly of MCC and of other mitotic checkpoint complexes.  We are also investigating how that different mitotic checkpoint complexes inhibit the action of the APC/C ubiquitin ligase. Since many cancer cells are characterized by aneuploidy, caused by defects in chromosome segregation, the results of this investigation may have implication in cancer.