The faithful segregation of chromosomes is the key event of mitosis, and its dysregulation can lead to aneuploidy and genomic instability, both hallmarks of cancer cells. A fundamental component in genome distribution during cell division is the centromere. Proteinaceous complexes known as kinetochores that form on centromeric chromatin generate a dynamic interface with spindle microtubules to segregate chromosomes to each daughter cell. Signalling pathways emanating from centromeric chromatin detect and correct errors in the geometry of chromosome-spindle microtubule attachments and prevent cell cycle progression until all chromosomes are properly connected. A key player in this process is the kinase Aurora B, which is part of the Chromosomal Passenger Complex (CPC) and resides at the centromeric chromatin between two joined sister chromatids. Histone modification and chromatin structure control the localization, abundance and activity of Aurora B at the centromere. Aurora B phosphorylates targets that regulate kinetochore-microtubule attachment to release erroneous geometries. However, the mechanism of error sensing and the role of centromeric chromatin is a matter of debate. The proposed work will focus on defining the mechanisms by which centromeric chromatin functions as a scaffold to coordinate kinetochore assembly, microtubule attachment, and the detection and repair of erroneous attachments. The impact of mitotic histone modifications on chromatin structure and their roles in centromeric identity will be analyzed through in vitro reconstitution with purified proteins and in Xenopus egg extracts. The mechanism of chromatin binding by the CPC and its role in Aurora B kinase activation at the centromere will also be analyzed using a combination of structural and biochemical approaches. The mechanism by which the CPC responds to and senses tension applied by spindle microtubules to kinetochores will be examined in the Xenopus extract system and genetically defined human cells and elucidated with the development of techniques to globally define Aurora B substrates in response to microtubule poisons.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
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National Cancer Institute Division of Basic Sciences
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