An Attachment-Independent Biochemical Timer of the Spindle Assembly Checkpoint

• DOI: 10.1016/j.molcel.2017.10.011
• Publication Date: 2017-11-09T13:52:38Z
• Authors: Junbin Qian; Maria Adelaida Ga...; Monique Beullens; Maria Giulia Manz...; Gerd Van der Hoeven; Juan Carlos Igual; Miguel Heredia; Pascual Sanz; Lendert Gelens; Mathieu Bollen
• Keywords: BUB1; Spindle checkpoint; Timer; PLK1; Prometaphase

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.