Jun-yong Huang

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Faulty cell division leads to aneuploidy and genetic instabilities that contribute to the progression of cancers and many other diseases including birth defects and Alzheimer's. To prevent this from happening, cells have evolved a mitotic surveillance mechanism, the spindle assembly checkpoint (SAC), to ensure a mother cell segregates its duplicated genomes equally into its two daughter cells with high fidelity during cell division. Many important proteins involved in this process have been identified, but exactly how they relay signals to coordinate the faithful mitotic progression still remain to be answered. Our lab uses biochemical, genetic, transgenic and microscopic methods to tackle these problems in human cells and Drosophila melanogaster (the fruit fly). The SAC mechanism involves the proteins Mad2, BubR1 and Cdc20. Mad2 and BubR1 are inhibitors of the APC/C, an E3 ubiquitin ligase, while Cdc20 is an activator. Once activated, the SAC can inactivate the APC/C to prevent destruction of two major mitotic regulators, Cyclin B and Securin, thus delaying the sister chromatid segregation. We have shown that the destruction of the Cyclin B is spatially and temporally regulated and that two APC/C core subunits, Cdc27 and Cdc16 are not always colocalised within cells. Cdc27 associates with mitotic chromosomes, but Cdc16 does not. This raises an intriguing possibility, that the activity of the mitotic APC/C is also spatially and temporally regulated. We have also shown that the SAC component BubR1, but not Mad2, is required for Cdc20 kinetochore recruitment. This provides an important new insight into the SAC mechanism. The functional interactions between the SAC mechanism and the apoptosis pathway are also under investigation.