A new dawn for Aurora B regulation: shining light on multiple discrete populations of Aurora B kinase at centromeres and kinetochores
Date
2020
Authors
Broad, Amanda J., author
DeLuca, Jennifer G., advisor
Luger, Karolin, committee member
Markus, Steven, committee member
Yao, Tingting, committee member
Amberg, Greg, committee member
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Abstract
Cell division is a fundamental biological process that is essential for all eukaryotes to divide the replicated genome with high fidelity into individual daughter cells. Improper segregation of replicated DNA results in chromosome instability, a characteristic that is deleterious to most cells. Critical to the proper segregation of mitotic chromosomes is attachment to spindle microtubules, which are dynamic cytoskeleton filaments that drive the movement of chromosomes during mitosis. A complex network of proteins, collectively called the kinetochore, mediates microtubule attachments to chromosomes. Kinetochores are recruited to individual chromosomes through a specialized heterochromatin domain known as the centromere. Centromeric heterochromatin is comprised of both canonical, H3-containing nucleosomes as well as nucleosomes that contain the histone H3 variant CENP-A. Centromeres serve as a central point of organization in mitotic cells, recruiting both structural and regulatory kinetochore proteins to chromosomes. This extensive protein/DNA network ensures the accurate segregation of chromosomes by regulation of proper kinetochore-microtubule attachments in mitosis. Kinetochore-microtubule interactions are regulated by Aurora B kinase, which phosphorylates outer kinetochore substrates to promote release of erroneous attachments. Although Aurora B kinase substrates at the kinetochore are defined, little is known about how Aurora B is recruited to and evicted from kinetochores, in early and late mitosis, respectively, to regulate these essential interactions. We set out to determine how Aurora B kinase is regulated during mitosis. We found that, contrary to the current model, Aurora B kinase and the Chromosomal Passenger Complex are recruited to distinct regions within the centromere and kinetochore. Furthermore, we found that accumulation of Aurora B kinase at centromeres is independent from Aurora B localization and activity at outer kinetochores. These results lead us to hypothesize a new model for Aurora B kinase regulation. In the direct recruitment model, a population of the kinase is recruited directly to kinetochores in early mitosis, then as mitosis progresses and kinetochore-microtubule attachments are stabilized, architectural changes within the kinetochore result in the eviction of outer-kinetochore localized Aurora B kinase and the stabilization of kinetochore-microtubule attachments.
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Subject
mitosis
Aurora B kinase