title: Premature Sister Chromatid Separation Is Poorly Detected by the Spindle Assembly Checkpoint as a Result of System-Level Feedback.
abstract: Sister chromatid cohesion, mediated by the cohesin complex, is essential for faithful mitosis. Nevertheless, evidence suggests that the surveillance mechanism that governs mitotic fidelity, the spindle assembly checkpoint (SAC), is not robust enough to halt cell division when cohesion loss occurs prematurely. The mechanism behind this poor response is not properly understood. Using developing Drosophila brains, we show that full sister chromatid separation elicits a weak checkpoint response resulting in abnormal mitotic exit after a short delay. Quantitative live-cell imaging approaches combined with mathematical modeling indicate that weak SAC activation upon cohesion loss is caused by weak signal generation. This is further attenuated by several feedback loops in the mitotic signaling network. We propose that multiple feedback loops involving cyclin-dependent kinase 1 (Cdk1) gradually impair error-correction efficiency and accelerate mitotic exit upon premature loss of cohesion. Our findings explain how cohesion defects may escape SAC surveillance.
authors.affiliation: Instituto Gulbenkian de Ciência, Rua da Quinta Grande, 2780-156 Oeiras, Portugal.
authors.forename: Mihailo
authors.initials: M
authors.lastname: Mirkovic
authors.affiliation: Department of Biochemistry, Oxford Center for Integrative Systems Biology, University of Oxford, Oxford OX1 3QU, UK.
authors.forename: Lukas H
authors.initials: LH
authors.lastname: Hutter
authors.affiliation: Department of Biochemistry, Oxford Center for Integrative Systems Biology, University of Oxford, Oxford OX1 3QU, UK.
authors.forename: Béla
authors.initials: B
authors.lastname: Novák
authors.affiliation: Instituto Gulbenkian de Ciência, Rua da Quinta Grande, 2780-156 Oeiras, Portugal. Electronic address: rcoliveira@igc.gulbenkian.pt.
authors.forename: Raquel A
authors.initials: RA
authors.lastname: Oliveira
mesh_terms: D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D002842:Chromatids / Q000235:genetics*; D059006:Chromosomes, Insect / Q000235:genetics*; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins; D025461:Feedback, Physiological; D059566:M Phase Cell Cycle Checkpoints; D008962:Models, Theoretical; D008941:Spindle Apparatus / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D016203:CDC2 Protein Kinase; C000601753:Cdk1 protein, Drosophila