Bub1 kinase activity drives error correction and mitotic checkpoint control but not tumor suppression
Robin M Ricke1, Karthik B Jeganathan, Liviu Malureanu
1Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN 55905, USA.
The Journal of Cell Biology
|December 5, 2012
Summary
Bub1 kinase activity is crucial for accurate chromosome segregation by controlling error correction and checkpoint signaling. However, its absence does not increase tumor susceptibility, revealing distinct roles in chromosome instability and tumor suppression.
Area of Science:
- Cell Biology
- Genetics
- Molecular Biology
Background:
- The mitotic checkpoint protein Bub1 is vital for cell proliferation and embryogenesis.
- Deviations in Bub1 levels lead to chromosome missegregation, aneuploidy, and cancer predisposition in mice.
Purpose of the Study:
- To investigate the physiological significance of Bub1 kinase activity at a modular level.
- To understand how Bub1's kinase function integrates error correction and checkpoint signaling.
Main Methods:
- Generated Bub1 mutant mice lacking kinase activity via gene targeting, maintaining normal protein levels.
- Analyzed chromosome segregation, aneuploidy, and tumor susceptibility in these mutant mice.
Main Results:
- Bub1 kinase activity controls Aurora B kinase localization and activity via histone H2A phosphorylation (T121), integrating attachment error correction and mitotic checkpoint signaling.
- Mice lacking Bub1 kinase activity showed significant chromosome segregation errors and aneuploidy.
- Despite aneuploidy, these mice did not exhibit increased susceptibility to spontaneous or carcinogen-induced tumors.
Conclusions:
- Bub1 kinase activity orchestrates distinct networks safeguarding against chromosome instability.
- The role of Bub1 in tumor suppression is differentially dependent on its kinase activity versus its protein abundance.
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