How the checkpoint holds mitosis
Unattached or tensionless kinetochores recruit Mad1, Mad2, BubR1, and Bub3. These proteins inhibit the anaphase-promoting complex (APC/C), the ubiquitin ligase that would otherwise trigger separase to cleave cohesin and separate sister chromatids. As long as any kinetochore is unsatisfied, APC/C stays off and the cell remains in metaphase. Microtubule poisons continuously create attachment errors, so the checkpoint never silences.
What sustained arrest produces
Prolonged mitotic arrest is not a resting state. The cell can slip out of mitosis without dividing, or it can die. The characteristic outcome is mitotic catastrophe: a failed division that leaves fragmented nuclei, micronuclei, or a tetraploid cell, which then triggers apoptosis. In other cells, sustained arrest directly engages the intrinsic apoptotic pathway. The lethal event is a mitosis that cannot finish, not DNA damage.
Why dividing cells are preferentially killed
The spindle is required only during M phase. A cell that divides frequently passes through M phase repeatedly and meets the drug's target many times; a quiescent cell in G0 rarely does. Selectivity comes from how often a cell enters the vulnerable phase, not from any recognition of cancer identity. This is the same phase-frequency logic that made antimetabolites S-phase-specific, and it is why microtubule poisons are scheduled to keep drug present across successive divisions.
Two chemistries, one functional outcome
Destabilizers (vinca alkaloids)
- Bind the vinca domain on tubulin
- Prevent dimer addition; depolymerize at high concentration
- At clinical concentrations, mainly suppress dynamic instability
- Spindle cannot build or remodel attachments
Stabilizers (taxanes)
- Bind a distinct pocket on \(\beta\)-tubulin
- Over-stabilize the polymer and prevent shortening
- Also suppress the growth–shrink switching
- Spindle cannot correct or release attachments
Why both classes arrest cells
Because the SAC responds to attachment and tension, not to the amount of polymer, a spindle that is too stable and a spindle that is too unstable both fail the checkpoint. This is why vincristine and paclitaxel — opposite in direct chemistry — share the same downstream consequence of mitotic arrest.