An Attachment-Independent Biochemical Timer of the Spindle Assembly Checkpoint

作者：Qian Junbin; Adelaida Garcia Gimeno Maria; Beullens Monique; Manzione Maria Giulia; Van der Hoeven Gerd; Carlos Igual Juan; Heredia Miguel; Sanz Pascual; Gelens Lendert; Bollen Mathieu

来源：Molecular Cell, 2017, 68(4): 715-+.

DOI：10.1016/j.molcel.2017.10.011

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.

• 出版日期2017-11-16