Bub1 kinase activity drives error correction and mitotic checkpoint control but not tumor suppression.

Authors:
Robin M Ricke
Robin M Ricke
University of Minnesota
United States
Karthik B Jeganathan
Karthik B Jeganathan
Mayo Clinic
United States
Liviu Malureanu
Liviu Malureanu
Mayo Clinic
United States
Dr Andrew M Harrison, MD, PhD
Dr Andrew M Harrison, MD, PhD
Mayo Clinic
Postdoctoral researcher
Clinical Informatics
Rochester, MN | United States

J Cell Biol 2012 Dec 3;199(6):931-49. Epub 2012 Dec 3.

Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN 55905, USA.

The mitotic checkpoint protein Bub1 is essential for embryogenesis and survival of proliferating cells, and bidirectional deviations from its normal level of expression cause chromosome missegregation, aneuploidy, and cancer predisposition in mice. To provide insight into the physiological significance of this critical mitotic regulator at a modular level, we generated Bub1 mutant mice that lack kinase activity using a knockin gene-targeting approach that preserves normal protein abundance. In this paper, we uncover that Bub1 kinase activity integrates attachment error correction and mitotic checkpoint signaling by controlling the localization and activity of Aurora B kinase through phosphorylation of histone H2A at threonine 121. Strikingly, despite substantial chromosome segregation errors and aneuploidization, mice deficient for Bub1 kinase activity do not exhibit increased susceptibility to spontaneous or carcinogen-induced tumorigenesis. These findings provide a unique example of a modular mitotic activity orchestrating two distinct networks that safeguard against whole chromosome instability and reveal the differential importance of distinct aneuploidy-causing Bub1 defects in tumor suppression.

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http://dx.doi.org/10.1083/jcb.201205115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518220PMC

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December 2012
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