Abstract
The spindle assembly checkpoint (SAC) ensures proper chromosome segregation by delaying anaphase onset in response to unattached kinetochores. Checkpoint signalling requires the kinetochore localization of the Mad1–Mad2 complex that in more complex eukaryotes depends on the Rod–Zwilch–ZW10 (RZZ) complex. The kinetochore protein Zwint has been proposed to be the kinetochore receptor for RZZ, but here we show that Bub1 and not Zwint is required for RZZ recruitment. We find that the middle region of Bub1 encompassing a domain essential for SAC signalling contributes to RZZ localization. In addition, we show that a distinct region in Bub1 mediates kinetochore localization of BubR1 through direct binding, but surprisingly removal of this region increases checkpoint strength. Our work thus uncovers how Bub1 coordinates checkpoint signalling by distinct domains for RZZ and BubR1 recruitment and suggests that Bub1 localizes antagonistic checkpoint activities.
Highlights
The spindle assembly checkpoint (SAC) ensures proper chromosome segregation by delaying anaphase onset in response to unattached kinetochores
Recent data have implicated a novel role of BubR1 in SAC silencing through its direct binding to the B56–PP2A phosphatase to initiate dephosphorylation of the MELT repeats either directly or through stimulating protein phosphatase 1 binding to KNL1
The lack of a stable Bub1– Mad1/2 interaction in human cells could be due to the presence of the Rod–Zwilch–ZW10 (RZZ) complex that is only present in complex eukaryotes and contributes to Mad1/2 kinetochore localization and checkpoint signalling[34,35,36,37]
Summary
The spindle assembly checkpoint (SAC) ensures proper chromosome segregation by delaying anaphase onset in response to unattached kinetochores. The lack of a stable Bub1– Mad1/2 interaction in human cells could be due to the presence of the Rod–Zwilch–ZW10 (RZZ) complex that is only present in complex eukaryotes and contributes to Mad1/2 kinetochore localization and checkpoint signalling[34,35,36,37]. The RZZ complex is bound to the dynein complex through the adaptor protein Spindly and the dynein complex can strip the RZZ from kinetochores through minus end-directed transport along kinetochore microtubules[38,39,40,41,42,43] This dynein-mediated stripping removes the Mad1/2 complex and contributes to checkpoint silencing but Mad1/2 can be removed by a dynein-independent mechanism[38,40]. The identification of ZW10 mutants that fail to bind Zwint yet still localize to kinetochores, less stably, suggests that additional kinetochore components contribute to RZZ localization[46]
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