The Spindle-Assembly Checkpoint and Chromosomal Instability

What the Checkpoint Senses

During mitosis each chromosome must attach to microtubules from opposite spindle poles. Kinetochores that are unattached, or attached without tension, recruit checkpoint proteins and emit a wait signal.

That signal assembles the mitotic checkpoint complex, containing MAD2, BUBR1 (encoded by BUB1B), BUB3 and CDC20, which inhibits the anaphase-promoting complex/cyclosome (APC/C).

How the Signal Is Released

Once every kinetochore is properly attached, the wait signal stops, the APC/C is freed, and it triggers destruction of securin and cyclin B. Loss of securin activates separase, which cleaves the cohesin holding sister chromatids together, and anaphase begins.

Because APC/C activation is essentially irreversible, the checkpoint must be fully satisfied before it happens; a single unattached kinetochore is enough to hold the whole cell.

A Weak Checkpoint and Chromosomal Instability

Reduced SAC strength lets cells enter anaphase before attachments are correct, producing daughter cells with extra or missing chromosomes. Ongoing errors of this kind are termed chromosomal instability (CIN) and are found in most solid tumours.

CIN can accelerate tumour evolution and drug resistance by generating heterogeneity, but excessive missegregation is lethal, giving a window of tolerable instability rather than an all-or-nothing effect.

Why Cancer Cells Still Need the SAC

Complete loss of the SAC causes catastrophic missegregation and death. Studies knocking down BUB1B in breast cancer cells show loss of viability, while normal cells are less affected, suggesting a therapeutic window.

This underlies interest in MPS1/TTK inhibitors and other mitotic-checkpoint drugs, which aim to push an already-unstable tumour past the survivable limit.

Interpretation Notes

SAC-gene expression changes and aneuploidy scores are research metrics; there is no simple one-to-one link between a SAC alteration and a clinical decision.

Constitutional biallelic BUB1B variants cause mosaic variegated aneuploidy syndrome, a rare condition distinct from somatic checkpoint changes in a tumour, and the two should not be conflated.

Key Takeaways

• ·The SAC blocks anaphase until all kinetochores are correctly attached.
• ·A weakened SAC produces chromosomal instability, common in aggressive cancers.
• ·Cancer cells retain a partial SAC and can be vulnerable to further checkpoint inhibition.
• ·SAC metrics are research tools, not standalone clinical guidance.