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

Mirkovic, Mihailo; Hutter, Lukas H.; Novák, Béla; Oliveira, Raquel A.

http://hdl.handle.net/10400.7/657

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Abstract(s)

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.

Keywords

Sister chromatid separation Drosophila SAC mitosis

URI

http://hdl.handle.net/10400.7/657

Citation

Mihailo Mirkovic, Lukas H. Hutter, Béla Novák, Raquel A. Oliveira, Premature Sister Chromatid Separation Is Poorly Detected by the Spindle Assembly Checkpoint as a Result of System-Level Feedback, Cell Reports, Volume 13, Issue 3, 20 October 2015, Pages 469-478, ISSN 2211-1247, http://dx.doi.org/10.1016/j.celrep.2015.09.020. (http://www.sciencedirect.com/science/article/pii/S2211124715010311)