Title: An Attachment-Independent Biochemical Timer of the Spindle Assembly Checkpoint
Authors: Qian, Junbin ×
García-Gimeno, Maria Adelaida
Beullens, Monique
Manzione, Maria Giulia
Van der Hoeven, Gerd
Igual, Juan Carlos
Heredia, Miguel
Sanz, Pascual
Gelens, Lendert
Bollen, Mathieu #
Issue Date: Nov-2017
Publisher: Cell Press
Series Title: Molecular Cell vol:68 issue:4 pages:715-730.e5
Article number: S1097-2765(17)30760-8
Abstract: 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.
ISSN: 1097-2765
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Dynamics in Biological Systems
Laboratory of Translational Genetics (VIB-KU Leuven Center for Cancer Biology)
Laboratory of Biosignaling & Therapeutics
× corresponding author
# (joint) last author

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