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

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Teaser

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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