3 years ago

An Attachment-Independent Biochemical Timer of the Spindle Assembly Checkpoint

An Attachment-Independent Biochemical Timer of the Spindle Assembly Checkpoint
The spindle assembly checkpoint (SAC) generates a diffusible protein complex that prevents anaphase until all chromosomes are properly attached to spindle microtubules. A key step in SAC initiation is the recruitment of MAD1 to kinetochores, which is generally thought to be governed by the microtubule-kinetochore (MT-KT) attachment status. However, we demonstrate that the recruitment of MAD1 via BUB1, a conserved kinetochore receptor, is not affected by MT-KT interactions in human cells. Instead, BUB1:MAD1 interaction depends on BUB1 phosphorylation, which is controlled by a biochemical timer that integrates counteracting kinase and phosphatase effects on BUB1 into a pulse-generating incoherent feedforward loop. We propose that this attachment-independent timer serves to rapidly activate the SAC at mitotic entry, before the attachment-sensing MAD1 receptors have become fully operational. The BUB1-centered timer is largely impervious to conventional anti-mitotic drugs, and it is, therefore, a promising therapeutic target to induce cell death through permanent SAC activation.

Graphical abstract



Qian et al. show that the spindle assembly checkpoint is governed by consecutive timer and sensor mechanisms. The timer involves the attachment-independent pulse phosphorylation of BUB1. They propose that the timer serves to activate the checkpoint before attachment-dependent sensor mechanisms become operational.

Publisher URL: www.sciencedirect.com/science

DOI: S1097276517307608

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