6533b85bfe1ef96bd12bb4bd
RESEARCH PRODUCT
An Attachment-Independent Biochemical Timer of the Spindle Assembly Checkpoint.
Junbin QianPascual SanzGerd Van Der HoevenMiguel López De HerediaMathieu BollenMonique BeullensMaria Giulia ManzioneMaria Adelaida Garcia-gimenoJuan Carlos IgualLendert Gelenssubject
0301 basic medicineMad1KinetochoreBUB1Nuclear ProteinsCell Cycle ProteinsCell BiologySpindle ApparatusBiologyProtein Serine-Threonine KinasesCell biologySpindle apparatus03 medical and health sciencesSpindle checkpoint030104 developmental biology0302 clinical medicineHEK293 CellsHumansTimerKinetochoresMolecular BiologyMitosis030217 neurology & neurosurgeryAnaphaseHeLa Cellsdescription
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. ispartof: Molecular Cell vol:68 issue:4 pages:715-730 ispartof: location:United States status: published
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2017-11-01 | Molecular cell |