Protein dynamics at the kinetochore: cell cycle regulation of the metaphase to anaphase transition

The spindle checkpoint blocks the initiation of anaphase in mitosis and mei osis if chromosomes are not aligned at the metaphase plate, The checkpoint functions by preventing a ubiquitin ligase called the anaphase-promoting co mplex/cyclosome (APC/C) from ubiquitinylating proteins whose destruction is required for anaphase onset, The spindle checkpoint signal originates at t he kinetochores of unaligned chromosomes and is broadcast to the rest of th e cell. Although the spindle checkpoint is not understood in detail, severa l components of the checkpoint-signaling pathway have been identified. Many of these components associate transiently with the kinetochores of unalign ed chromosomes, We propose a model in which kinetochores that lack stable a ttachments to the spindle microtubules serve as catalytic staging areas for the assembly of inhibitor complexes. These inhibitor complexes then leave the kinetochores and block activity of the APC/C throughout the cell. We su ggest that microtubule occupancy at kinetochores or physical tension induce d by microtubule capture turns off the capability of the kinetochore to pro duce the APC/C inhibitor. Subsequently, the inhibitor concentration in the cell wanes and anaphase initiates.