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Abstract:
In eukaryotes, the spindle assembly checkpoint (SAC) is crucial to ensure fidelity of chromosome segregation in mitosis. Malfunction of this checkpoint leads to chromosome segregation errors and has been implicated in tumorigenesis. Given its central importance, this checkpoint should withstand stochastic fluctuations in intracellular protein abundance as well as environmental perturbations, but the extent and mechanisms of its robustness are unknown. We probed spindle assembly checkpoint signaling after modulating checkpoint protein abundance and nutrient conditions in fission yeast. The checkpoint tolerates individual SAC protein abundance changes to different degrees. For core checkpoint proteins, a mere 20 % reduction in abundance can suffice to perturb signaling, revealing a surprising fragility. Quantification of protein abundance in single cells showed that the variability (‘noise’) of critical checkpoint proteins is kept within a narrow window, explaining why the checkpoint normally functions reliably. When checkpoint signaling was perturbed by protein abundance changes, single cells within a genetically identical population varied strongly in their response, from fully functional to completely abolished checkpoint signaling. This reveals that the inherent 'noisiness' of cells can drastically affect spindle assembly checkpoint signaling, at least in perturbed situations. Our work highlights low gene expression noise as one important determinant of reliable checkpoint signaling and provides a basis to understand checkpoint signaling in a natural environment.
