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Centromeres: unique chromatin structures that drive chromosome segregation

Nature Reviews Molecular Cell Biology volume 12, pages 320–332 (2011)Cite this article

Subjects

Key Points

  • Eukaryotic centromeres are regions on chromosomes that mark the site of kinetochore formation, which in turn attach to the mitotic spindle. Centromere-associated proteins assemble hierarchically onto the chromatin and connect the chromosome to the outer kinetochore.

  • The centromeric and pericentromeric chromatin are defined by histone variants (for example, centromeric protein A (CENPA) and H2A.Z) and patterns of histone modifications, such as methylation. The histone H3 variant CENPA is found at all eukaryotic centromeres and is required for centromere function. Various different structures have been proposed for the organization of the CENPA-containing nucleosome.

  • Research is beginning to elucidate the mechanisms of CENPA loading and will further our understanding of the roles of loading factors such as KNL2, Holliday junction recognition protein (suppressor of chromosome missegregation 3 in yeast) and histone remodellers and chaperones.

  • The geometry of the centromeric chromatin aids in bi-orientation of sister chromatids and tension-sensing across the mitotic spindle, and cohesin and histone variants are known to play a part in defining this organization.

  • Entropic forces are important for organizing the whole chromosome into loops. These forces also have a role in chromosome segregation by driving the chromosomes apart, with directionality and timing, from the mitotic spindle.

  • The centromeric chromatin, with the packaging proteins, must balance the outwards forces applied by the mitotic spindle to ensure fidelity in chromosome segregation without breakage. The inwards force can be characterized by springs composed of both DNA and protein elements.

Abstract

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.

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Figure 1: Chromosome segregation in the cell cycle.
Figure 2: Characteristics of point and regional centromeres.
Figure 3: The CENPA-containing nucleosome.
Figure 4: Chromatin geometry at the centromere.
Figure 5: Applying the principles of polymer physics to chromosome segregation.

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Acknowledgements

We thank the members of the Bloom laboratory for discussions and editorial suggestions. We also thank the anonymous referees for their useful comments. We apologize to those authors whose work was not included owing to space limitations. This work was supported by the US National Institutes of Health.

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  1. Department of Biology, 622 Fordham Hall, CB3280, University of North Carolina at Chapel Hill, 27599, North Carolina, USA

    Jolien S. Verdaasdonk & Kerry Bloom

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Glossary

Kinetochore

A multiprotein complex that assembles on centromeric DNA and mediates the attachment and movement of chromosomes along the microtubules of the mitotic spindle.

Holocentric chromosomes

Chromosomes lacking a localized centromere and primary constriction site. In holocentric chromosomes, kinetochores are diffuse and kinetochore microtubules attach along the length of the chromosome.

Centrosomes

Specialized organelles that duplicate during interphase and that constitute the centre of the mitotic spindle.

Centromeric chromatin

The chromatin where centromeric protein A is incorporated, underlying the kinetochore.

Pericentromeric chromatin

The chromatin flanking the centromeric chromatin.

Nucleosome

The basic structural subunit of chromatin, which consists of ∼147 base pairs of DNA wrapped ∼1.7 times around an octamer of histones (2 copies each of H2A, H2B, H3 and H4).

Satellite repeats

Specific DNA sequences that are repeated many times in long tandem arrays.

Dicentric chromosome

A chromosome that carries two centromeres, which arise from the aberrant fusion of 'naked' telomeres or interstitial double-strand breaks. These can also be experimentally generated by inserting a second conditional centromere into a chromosome.

Position effect variegation

Variable expression of DNA sequence based on temporal or quantitative effects from adjacent chromatin; for example, if an active gene is relocated to a heterochromatic region, it can randomly be silenced

Tetrasomes

(Homotypic tetramers). Proposed nucleosome structures found at the centromere and composed of two copies each of centromeric protein A and H4.

Hemisome

(Heterotypic tetramer). A proposed nucleosome structure found at the centromere and composed of one copy each of H2A, H2B, centromeric protein A and H4.

Homotypic octamers

In the context of nucleosome composition, octamers in which both copies of H3 have been replaced by centromeric protein A.

Heterotypic octamer

In the context of nucleosome composition, an octamer in which only one copy of H3 has been replaced by centromeric protein A.

Amphitelic attachment

Connection of sister kinetochores to microtubules that emanate from opposite spindle pole bodies.

Intramolecular loop

A loop of chromatin formed by bringing distant regions of the same sister chromatid together, as opposed to intermolecular interactions between sister chromatid pairs. It is the proposed structure of the pericentromeric chromatin in budding yeast.

Entropy

A thermodynamic property related to the state of disorder of a system.

Thermal motion

The random motion and collision of particles owing to temperature.

Young's modulus

(Also known as elastic modulus). A measure of the stiffness of a polymer, measured as stress divided by strain.

Stress

In the context of polymer physics, stress is defined as the force per unit area and measures how a material responds to external force.

Strain

In the context of polymer physics, strain measures the deformation of the material, measured as change in length over length (ΔL/L).

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Verdaasdonk, J., Bloom, K. Centromeres: unique chromatin structures that drive chromosome segregation. Nat Rev Mol Cell Biol 12, 320–332 (2011). https://doi.org/10.1038/nrm3107

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