Feedback Control in Sensing Chromosome Biorientation by the Aurora B Kinase

Abstract

Maintenance of genome stability during cell division depends on establishing correct attachments between chromosomes and spindle microtubules. Correct, bi-oriented attachments are stabilized, while incorrect attachments are selectively destabilized. This process relies largely on increased phosphorylation of kinetochore substrates of Aurora B kinase at misaligned versus aligned kinetochores. Current models explain this differential phosphorylation by spatial changes in the position of substrates relative to a constant pool of kinase at the inner centromere. However, these models are based on studies in aneuploid cells. We show that normal diploid cells have a more robust error correction machinery. Aurora B is enriched at misaligned centromeres in these cells, and the dynamic range of Aurora B substrate phosphorylation at misaligned versus aligned kinetochores is increased. These findings indicate that in addition to Aurora B regulating kinetochore-microtubule binding, the kinetochore also controls Aurora B recruitment to the inner centromere. We show that this recruitment depends on both activity of Plk1, a kinetochore-localized kinase, and activity of Aurora B itself. Our results suggest a feedback mechanism in which Aurora B both regulates and is regulated by chromosome attachment to the spindle, which amplifies the differential phosphorylation of kinetochore substrates and increases the efficiency of error correction.

EB1 acetylation by P300/CBP-associated factor (PCAF) ensures accurate kinetochore–microtubule interactions in mitosis

“…This array of cargo proteins implies the existence in mitosis of a complex but coordinated regulation to ensure chromosome segregation. We and others have shown that the mitotic kinases, PLK1 and Aurora B, form a feedback loop to control MCAK, a microtubule regulator (20,26,27). As established here, acetyl regulation of the K220-SxIP interaction is another layer of fidelity control in mitotic chromosome plasticity.…”

Haspin kinase regulates microtubule-organizing center clustering and stability through Aurora kinase C in mouse oocytes

“…The following primary antibodies were used in immunofluorescence: CREST autoimmune serum (Antibodies Incorporated; #15-234; 1:30), anti-AURKC (Bethyl #A400-023A-BL1217; 1:30) antibody, anti-α-tubulinAlexa-Fluor-488 conjugate (Life Technologies #322588; 1:100), and antipericentrin (BD Biosciences #611814; 1:100), anti-γ-tubulin (Sigma #T6557; 1:100), anti-AURKA (Bethyl A300-072A; 1:30), anti-pAURKA (Cell Signaling #3079S; 1:30), anti-pINCENP (gift of Michael Lampson, University of Pennsylvania, Philadelphia, PA; 1:1000; Salimian et al, 2011) and anti-survivin (Cell Signaling Technology #2808S; 1:500) antibodies.…”

A mathematical model of Aurora B activity in prophase and metaphase

“…Including a spatially variable phosphatase concentration and also localisation of phosphatases to kinetochores could provide a much more sophisticated view of the opposing action of kinases and phosphatases at kinetochores. Aurora B is found at higher concentrations at improper kinetochore-microtubule attachments [40,95,105] . Therefore, a natural extension of a model which includes kinetochore-microtubule attachments would be to incorporate a dependence of the centromeric binding dynamics on the kinetochore-microtubule attachment state.…”