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      An Attachment-Independent Biochemical Timer of the Spindle Assembly Checkpoint.

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          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.

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          Author and article information

          Journal
          Mol. Cell
          Molecular cell
          Elsevier BV
          1097-4164
          1097-2765
          Nov 16 2017
          : 68
          : 4
          Affiliations
          [1 ] Laboratory of Biosignaling & Therapeutics, Department of Cellular and Molecular Medicine, University of Leuven, 3000 Leuven, Belgium. Electronic address: junbin.qian@kuleuven.be.
          [2 ] Departament de Biotecnologia, Universitat Politècnica de València, Camino de Vera, 14, 46022 Valencia, Spain.
          [3 ] Laboratory of Biosignaling & Therapeutics, Department of Cellular and Molecular Medicine, University of Leuven, 3000 Leuven, Belgium.
          [4 ] Departament de Bioquímica i Biologia Molecular and Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), Universitat de València, 46100 Burjassot (Valencia), Spain.
          [5 ] Instituto de Biomedicina de Valencia (CSIC), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Jaime Roig 11, 46010 Valencia, Spain.
          [6 ] Laboratory of Dynamics in Biological Systems, Department of Cellular and Molecular Medicine, University of Leuven, 3000 Leuven, Belgium.
          [7 ] Laboratory of Biosignaling & Therapeutics, Department of Cellular and Molecular Medicine, University of Leuven, 3000 Leuven, Belgium. Electronic address: mathieu.bollen@kuleuven.be.
          Article
          S1097-2765(17)30760-8
          10.1016/j.molcel.2017.10.011
          29129638
          25a6ac34-4170-4cd5-b20c-7057319361d5
          History

          BUB1,MPS1,PP2A-B56,anti-mitotic therapy,biochemical timer,microtubule-kinetochore attachment,mitosis,spindle assembly checkpoint

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