Abstract
Eukaryotic chromosome segregation relies upon specific connections from DNA to the microtubule-based spindle that forms at cell division. The chromosomal locus that directs this process is the centromere, where a structure called the kinetochore forms upon entry into mitosis. Recent crystallography and single-particle electron microscopy have provided unprecedented high-resolution views of the molecular complexes involved in this process. The centromere is epigenetically specified by nucleosomes harbouring a histone H3 variant, CENP-A, and we review recent progress on how it differentiates centromeric chromatin from the rest of the chromosome, the biochemical pathway that mediates its assembly and how two non-histone components of the centromere specifically recognize CENP-A nucleosomes. The core centromeric nucleosome complex (CCNC) is required to recruit a 16-subunit complex termed the constitutive centromere associated network (CCAN), and we highlight recent structures reported of the budding yeast CCAN. Finally, the structures of multiple modular sub-complexes of the kinetochore have been solved at near-atomic resolution, providing insight into how connections are made to the CCAN on one end and to the spindle microtubules on the other. One can now build molecular models from the DNA through to the physical connections to microtubules.
Highlights
Ensuring the faithful propagation of genetic information across generations is one of the most fundamental problems of cell biology
Each pair of sister chromatids must align along the metaphase plate and form proper attachments to spindle microtubules such that the sister chromatids segregate towards opposite poles, leaving one chromatid in each resultant daughter cell [2]
Moving out from chromatin towards the microtubules, the part of the kinetochore assembly is the inner kinetochore, which contains many CENP proteins organized in various subcomplexes including CENP-C, CENP-LN, CENP-HIKM, CENP-OPQUR and CENP-TWSX, together termed the constitutive centromere associated network (CCAN) [19,20,21,22,23,24,25,26,27,28,29,30,31]
Summary
Ensuring the faithful propagation of genetic information across generations is one of the most fundamental problems of cell biology. Moving out from chromatin towards the microtubules, the part of the kinetochore assembly is the inner kinetochore, which contains many CENP proteins organized in various subcomplexes including CENP-C, CENP-LN, CENP-HIKM, CENP-OPQUR and CENP-TWSX, together termed the constitutive centromere associated network (CCAN) (figure 1c) [19,20,21,22,23,24,25,26,27,28,29,30,31]. Our review addresses structural and biophysical features of the CENP-A nucleosome, the 16-subunit CCAN, and the manner in which these complexes form the basis for microtubule binding via the outer kinetochore and other microtubule-associated proteins. Recent advances in structural studies of the kinetochore have given us higher-resolution structures of individual kinetochore components They provide new details about how they interact with each other, with centromeric DNA and with spindle microtubules. We review this exciting progress and emphasize areas where the findings can be synthesized into emerging models for the mechanisms underlying chromosome segregation
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