- The spindle assembly checkpoint (SAC) is a central surveillance mechanism that ensures chromosomes are accurately segregated during mitosis. It prevents the onset of anaphase until every chromosome has achieved correct bi‑orientation and stable kinetochore–microtubule attachment. Without this checkpoint, cells would enter anaphase prematurely, leading to chromosome mis‑segregation, aneuploidy and long‑term genomic instability. The SAC therefore acts as a molecular brake that maintains genomic integrity and supports faithful cell division.
- During prometaphase, microtubules attach to kinetochores through a stochastic search‑and‑capture process. Because this process is inherently error‑prone, many kinetochores initially lack proper attachment or tension. These conditions activate SAC signalling. Key checkpoint proteins such as Mad1, Mad2, Bub1, BubR1 and Mps1 accumulate at unattached or tension‑free kinetochores, forming a signalling platform that inhibits the anaphase‑promoting complex/cyclosome (APC/C). This inhibition prevents the degradation of securin and cyclin B, thereby blocking separase activation and delaying sister chromatid separation.
- The SAC works in close coordination with mitotic error correction, which is driven by Aurora B kinase and the Chromosomal Passenger Complex. Aurora B destabilises incorrect kinetochore–microtubule attachments by phosphorylating outer‑kinetochore substrates. As error correction resolves faulty attachments, kinetochores gradually achieve proper bi‑orientation and generate tension. This tension reduces Aurora B’s access to its substrates, stabilising correct attachments and promoting SAC silencing.
- SAC silencing is a highly regulated process. Once all kinetochores are properly attached and under tension, checkpoint proteins dissociate from kinetochores, and the inhibitory signal to APC/C is lifted. APC/C–Cdc20 becomes active, triggering the degradation of securin and cyclin B. This allows separase to cleave cohesin, enabling sister chromatid separation and the onset of anaphase. The precise timing of SAC silencing is essential; premature silencing leads to mis‑segregation, while prolonged activation causes mitotic arrest and cell death.
- Although the SAC is highly effective, certain attachment errors—particularly merotelic attachments—can escape detection because they generate partial tension. These errors may persist into anaphase, producing lagging chromosomes and micronuclei. Such defects are common in cancer cells, which often exhibit weakened SAC signalling, altered kinetochore composition and mis‑regulated Aurora B activity. Tumour cells may tolerate low‑fidelity SAC responses, allowing them to accumulate chromosomal instability while continuing to proliferate.
- The SAC is also a major target in cancer therapy. Drugs that disrupt microtubule dynamics, such as taxanes and vinca alkaloids, activate the SAC by preventing proper kinetochore–microtubule attachment. Prolonged SAC activation leads to mitotic arrest and apoptosis in rapidly dividing tumour cells. Aurora B inhibitors, by contrast, weaken SAC signalling and overwhelm tumour cells with uncorrected segregation errors. Both strategies exploit the checkpoint’s central role in mitotic fidelity.
- In summary, the spindle assembly checkpoint is a tension‑sensing, kinetochore‑based surveillance system that prevents premature anaphase onset. By coordinating with Aurora B‑mediated error correction, the SAC ensures that all chromosomes achieve proper bi‑orientation before segregation. Its failure contributes to aneuploidy and cancer progression, while its controlled activation or inhibition forms the basis of several anti‑mitotic therapies.
