Practice question

Reliability of chromosome segregation depends on surveillance mechanism preventing anaphase until every chromosome correctly attached to spindle, because single missegregation yields aneuploid daughter prone to tumor development or cell death. Spindle assembly checkpoint monitors occupancy and tension at kinetochores, large protein structures assembled on CENP-A containing centromeric chromatin. Unattached kinetochores recruit Mad1-Mad2 complex that catalyzes conversion of cytosolic open Mad2 to closed form bound to Cdc20. Together with BubR1, Bub3, Mps1-phosphorylated Bub1 they assemble mitotic checkpoint complex MCC that diffuses to inhibit APC/C-Cdc20 ubiquitin ligase activity, blocking degradation of securin and cyclin B. Aurora B kinase at inner centromere phosphorylates Ndc80 complex under low tension destabilizing erroneous syntelic attachments, recreating unattached kinetochore that re-engages checkpoint. Upon biorientation where sister kinetochores attach to opposite poles generating tension, Mad1-Mad2 recruitment ceases, MCC disassembles, APC/C activates separase, and synchronous segregation proceeds, preventing errors. This circuitry is highly conserved across eukaryotes, integrating growth factor signals, DNA damage surveillance, and developmental cues, and its disruption frequently underlies oncogenesis, providing targets for checkpoint inhibitors and cancer therapeutics.