Premature Sister Chromatid Separation Is Poorly Detected by the Spindle Assembly Checkpoint as a Result of System-Level Feedback

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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. Mirkovic et al. show that premature loss of sister chromatid cohesion during mitosis does not trigger a robust checkpoint response. Quantitative live-cell imaging and mathematical modeling approaches describe several feedback loops between the error-correction machinery, the spindle assembly checkpoint (SAC), and Cdk1 that compromise the efficient detection of cohesion defects.

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Mirkovic, M., Hutter, L. H., Novák, B., & Oliveira, R. A. (2015). Premature Sister Chromatid Separation Is Poorly Detected by the Spindle Assembly Checkpoint as a Result of System-Level Feedback. Cell Reports, 13(3), 469–478. https://doi.org/10.1016/j.celrep.2015.09.020

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