Details

Autor(en) / Beteiligte

• 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

Titel

An Attachment-Independent Biochemical Timer of the Spindle Assembly Checkpoint

Ist Teil von

• Molecular cell, 2017-11, Vol.68 (4), p.715-730.e5

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2017

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Pulse phosphorylation of BUB1 transiently promotes MAD1 kinetochore recruitment•Phosphorylation of BUB1 by MPS1 is reversed by BUBR1-associated PP2A-B56•Delayed PP2A-B56 recruitment shapes an attachment-independent timer•Targeting cancer cells by disrupting the BUB1 timer holds therapeutic potential 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.