Practice question

Faithful chromosome segregation depends on physical linkage between centromeric DNA and spindle microtubules via kinetochore large protein machine exceeding 100 components organized into layered architecture. Inner kinetochore permanently bound to centromere during cell cycle contains constitutive centromere-associated network including CENP-C that recognizes CENP-A nucleosome, plus CENP-T-W-S-X tetramer forming DNA binding module with histone-like fold. Outer kinetochore assembled specifically in mitosis contains KMN network: Knl1 scaffold with MELT motifs recruiting checkpoint proteins, Mis12 complex bridging inner and outer layers, and Ndc80 complex heterotetramer of Ndc80, Nuf2, Spc24, Spc25 whose calponin homology domains bind microtubule lattice. Ska complex tracks depolymerizing ends converting microtubule shortening into pulling force. Sister kinetochores face back-to-back enabling amphitelic attachment to opposite poles. Kinase Aurora B corrects syntelic errors lacking tension by phosphorylating Ndc80 reducing affinity. Loss of Ndc80 interaction causes chromosome detachment and spindle checkpoint persistent activation. 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.