Kinetochore: Structure, Function and Evolution

Abstract

Duplicated eukaryotic chromosomes are segregated into daughter cells through cell division. Faithful chromosome segregation depends on kinetochores, which are specialized macromolecular structures built upon centromeric chromatin. The dynamic kinetochore structures connect chromosomes with spindle microtubules, power chromosome movement, and signal the activation and silencing of the spindle assembly checkpoint (SAC). Molecular analyses of the components and architecture of kinetochores have advanced rapidly in recent years. A human kinetochore contains approximately 200 proteins, many of which are evolutionarily conserved in other organisms. A histone H3 variant, CENP‐A and associated constitutive centromere proteins lay the foundation for kinetochore build‐up. Multiple kinetochore‐localised microtubule‐binding proteins including the Ndc80 complex help regulate chromosome movement. The SAC signalling originates from kinetochores and contributes to the fidelity of chromosome segregation. Many fascinating properties remain to be elucidated about the kinetochore as a fundamental machinery to maintain genomic stability. Key Concepts: Chromosome segregation in eukaryotic cells depends upon connecting spindle microtubules with special macromolecular structures on chromosomes called kinetochores. The centromere is the chromosomal locus where a kinetochore is built. Laying the foundation for kinetochore assembly at centromeres are CENP‐A (a histone H3 variant) containing nucleosomes and a group of CENP‐A associated proteins (termed constitutive centromere proteins). There are multiple microtubule motors and nonmotor microtubule‐binding proteins localised at kinetochores to coordinate chromosome movement. A 10 protein complex called KMN network is currently thought to provide the primary end‐on microtubule‐binding activity. The spindle assembly checkpoint (SAC) monitors the kinetochore–microtubule attachment and signals the delay of the metaphase‐to‐anaphase transition when defects are detected. Conformational change of MAD2 and assembly of the mitotic checkpoint complex (MCC) are the key events to activate the SAC. Comparative studies of similar and distinct kinetochore composition, structure and function in different species and during mitosis or meiosis have provided evolutionary perspectives on mechanisms regulating chromosome segregation.