The spindle assembly checkpoint (SAC) monitors kinetochore attachment to spindle microtubules, preventing anaphase until all chromosomes are bi-oriented (one sister chromatid pulled to each pole). Unattached or improperly attached kinetochores recruit Mad1/Mad2 complexes, which inhibit Cdc20 and prevent activation of the anaphase-promoting complex (APC), blocking cyclin B degradation and mitotic exit. Once all kinetochores are attached, Cdc20 is released, APC ubiquitinates cyclin B and securin, and anaphase proceeds with accurate chromosome segregation.
From your study of mitosis, you know that the goal of cell division is to deliver exactly one copy of every chromosome to each daughter cell. You also know from cell cycle checkpoints that the cell pauses at critical moments to verify that conditions are safe before proceeding. The spindle assembly checkpoint (SAC) is the specific checkpoint that operates during mitosis to answer one question: are all chromosomes properly attached to the spindle before we pull them apart? If even a single chromosome is misattached, the answer is no, and the cell halts at the metaphase-to-anaphase transition until the problem is corrected.
The mechanism works through a "wait" signal generated by unattached kinetochores — the protein structures on each chromosome where spindle microtubules grab hold. Each sister chromatid pair must achieve bi-orientation: one kinetochore attached to microtubules from one spindle pole, the other kinetochore attached to microtubules from the opposite pole. When a kinetochore lacks attachment or is attached to the wrong pole, it recruits checkpoint proteins — particularly Mad1 and Mad2. These proteins undergo a conformational change at the unattached kinetochore that converts Mad2 into an active inhibitor. Active Mad2 then sequesters Cdc20, a key activator of the anaphase-promoting complex (APC/C). Without Cdc20, the APC/C cannot function, and the cell stays locked in metaphase.
Think of it as a voting system where every kinetochore must signal "attached" before the cell proceeds. A single unattached kinetochore continuously produces the Mad2 inhibitory signal, which is amplified and spread throughout the cell. This means the checkpoint is exquisitely sensitive — one unattached chromosome out of 46 in a human cell is enough to block anaphase entirely. The signal is catalytic: the unattached kinetochore acts as a template that converts inactive Mad2 into active Mad2, which then diffuses away to inhibit Cdc20 throughout the cytoplasm.
Once all kinetochores achieve proper bi-oriented attachment and are under tension from opposing spindle poles, the "wait" signal stops. Cdc20 is released from inhibition and activates the APC/C, a ubiquitin ligase that tags two critical substrates for destruction: securin and cyclin B. Securin normally holds the enzyme separase in check — once securin is degraded, separase cleaves the cohesin rings that physically hold sister chromatids together, allowing them to be pulled to opposite poles. Cyclin B degradation inactivates Cdk1, which triggers mitotic exit: the spindle disassembles, chromosomes decondense, and the nuclear envelope reforms. When this checkpoint fails — through mutations in Mad or Bub proteins, for instance — cells can mis-segregate chromosomes, producing aneuploid daughter cells. This is a hallmark of many cancers, which is why the SAC is considered a critical tumor suppressor mechanism.