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An Attachment-Independent Biochemical Timer of the Spindle Assembly Checkpoint.
- Source :
-
Molecular Cell . Nov2017, Vol. 68 Issue 4, p715-730.e5. 1p. - Publication Year :
- 2017
-
Abstract
- Summary 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 10972765
- Volume :
- 68
- Issue :
- 4
- Database :
- Academic Search Index
- Journal :
- Molecular Cell
- Publication Type :
- Academic Journal
- Accession number :
- 126231862
- Full Text :
- https://doi.org/10.1016/j.molcel.2017.10.011