Fidelity during chromosome segregation is essential to prevent aneuploidy. The proteins and chromatin at the centromere form a unique site for kinetochore attachment and allow the cell to sense and correct errors during chromosome segregation. Centromeric chromatin is characterized by distinct chromatin organization, epigenetics, centromere-associated proteins and histone variants. These include the histone H3 variant centromeric protein A (CENPA), the composition and deposition of which have been widely investigated. Studies have examined the structural and biophysical properties of the centromere and have suggested that the centromere is not simply a ‘landing pad’ for kinetochore formation, but has an essential role in mitosis by assembling and directing the organization of the kinetochore.
Summary The organization of chromosomes into territories plays an important role in a wide range of cellular processes including gene expression, transcription, and DNA repair. Current understanding has largely excluded the spatio-temporal dynamic fluctuations of the chromatin polymer. We combine in vivo chromatin motion analysis with mathematical modeling to elucidate the physical properties that underlie the formation and fluctuations of territories. Chromosome motion varies in predicted ways along the length of the chromosome, dependent on tethering at the centromere. Detachment of a tether upon inactivation of the centromere results in increased spatial mobility. A confined bead-spring chain tethered at both ends provides a mechanism to generate observed variations in local mobility as a function of distance from the tether. These predictions are realized in experimentally determined higher effective spring constants closer to the centromere. The dynamic fluctuations and territorial organization of chromosomes are, in part, dictated by tethering at the centromere.
During mitosis, cohesin- and condensin-based pericentric chromatin loops function as a spring network to balance spindle microtubule force.
Background Tension sensing of bi-oriented chromosomes is essential for the fidelity of chromosome segregation. The spindle assembly checkpoint (SAC) conveys lack of tension or attachment to the anaphase promoting complex. Components of the SAC (Bub1) phosphorylate histone H2A (S121) and recruit the protector of cohesin, Shugoshin (Sgo1) to the inner centromere. How the chromatin structural modifications of the inner centromere are integrated into the tension sensing mechanisms and the checkpoint are not known. Results We have identified a Bub1/Sgo1 dependent structural change in the geometry and dynamics of kinetochores and the pericentric chromatin upon reduction of microtubule dynamics. The cluster of inner kinetochores contract while the pericentric chromatin and cohesin that encircle spindle microtubules undergo a radial expansion. Despite its increased spatial distribution, the pericentric chromatin is less dynamic. The change in dynamics is due to histone H2A phosphorylation and Sgo1 recruitment to the pericentric chromatin, rather than microtubule dynamics. Conclusions Bub1 and Sgo1 act as a rheostat to regulate the chromatin spring and maintain force balance. Through Histone H2A S121 phosphorylation and recruitment of Sgo1, Bub1 kinase softens the chromatin spring in response to changes in microtubule dynamics. The geometric alteration of all 16 kinetochores and pericentric chromatin reflect global changes in the pericentromeric region and provide mechanisms for mechanically amplifying damage at a single kinetochore microtubule.
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