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Bimodal activation of BubR1 by Bub3 sustains mitotic checkpoint signaling.

Proc Natl Acad Sci U S A.. 2014-10;  111(40):E4185-93
Han JS, Vitre B, Fachinetti D, Cleveland DW. Ludwig Institute for Cancer Research and Departments of Cellular and Molecular Medicine and Medicine, University of California, San Diego, La Jolla, CA 92093
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The mitotic checkpoint (also known as the spindle assembly checkpoint) prevents premature anaphase onset through generation of an inhibitor of the E3 ubiquitin ligase APC/C, whose ubiquitination of cyclin B and securin targets them for degradation. Combining in vitro reconstitution and cell-based assays, we now identify dual mechanisms through which Bub3 promotes mitotic checkpoint signaling. Bub3 enhances signaling at unattached kinetochores not only by facilitating binding of BubR1 but also by enhancing Cdc20 recruitment to kinetochores mediated by BubR1's internal Cdc20 binding site. Downstream of kinetochore-produced complexes, Bub3 promotes binding of BubR1's conserved, amino terminal Cdc20 binding domain ... More