The Spindle Assembly Checkpoint works like a rheostat not a toggle-switch

The Spindle Assembly Checkpoint (SAC) is essential in mammalian mitosis to ensure the equal segregation of sister chromatids(1, 2). The SAC generates a Mitotic Checkpoint Complex (MCC) to prevent the Anaphase Promoting Complex/Cyclosome (APC/C) from targeting key mitotic regulators for destruction until all the chromosomes have attached to the mitotic apparatus(1, 3, 4). A single unattached kinetochore can delay anaphase for several hours(5), but how it is able to block the APC/C throughout the cell is not understood. Current concepts of the SAC posit that it exhibits either an ‘all or nothing’ response(6) or there is a minimum threshold sufficient to block the APC/C(7). Here, we have used gene targeting to measure SAC activity and find that it does not have an ‘all or nothing’ response. Instead, the strength of the SAC depends on the amount of Mad2 recruited to kinetochores and on the amount of MCC formed. Furthermore, we show that different drugs activate the SAC to different extents, which may be relevant to their efficacy in chemotherapy.