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The molecular basis for centromere identity and function

Key Points

  • Centromeres are defined epigenetically and require the presence of the centromere-specific histone H3 variant centromere protein A (CENP-A).

  • Although DNA sequences are not strictly required for centromere specification, similarities in the organization of centromere DNA suggest that DNA structures contribute to centromere function.

  • CENP-A nucleosomes contain unique sequence and structural features that allow them to stably mark the centromere and be recognized by kinetochore components.

  • CENP-A propagation requires specialized deposition factors and tight regulatory control.

  • The centromere directs the assembly of the kinetochore via the 16-subunit constitutive centromere-associated network (CCAN).

Abstract

The centromere is the region of the chromosome that directs its segregation in mitosis and meiosis. Although the functional importance of the centromere has been appreciated for more than 130 years, elucidating the molecular features and properties that enable centromeres to orchestrate chromosome segregation is an ongoing challenge. Most eukaryotic centromeres are defined epigenetically and require the presence of nucleosomes containing the histone H3 variant centromere protein A (CENP-A; also known as CENH3). Ongoing work is providing important molecular insights into the central requirements for centromere identity and propagation, and the mechanisms by which centromeres recruit kinetochores to connect to spindle microtubules.

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Figure 1: Visualization of the centromere.
Figure 2: Centromere specification.
Figure 3: Specialization and propagation of centromere protein A (CENP-A).
Figure 4: Centromeric chromatin.
Figure 5: Contributions of the constitutive centromere-associated network (CCAN) at the centromere–kinetochore interface.

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Acknowledgements

The authors apologize to those colleagues whose work they were unable to describe owing to space constraints. They thank members of the Cheeseman laboratory for critical reading of the manuscript and helpful discussions, Bill Earnshaw for directing them to Cyril Darlington's description of the form and function of the centromere, and Conly Rieder, Alexey Khodjakov and Elaine Dunleavy for generously sharing micrographs. Work in the Cheeseman laboratory is supported by a Scholar award to I.M.C. from the Leukemia & Lymphoma Society, a grant from the U.S. National Institutes of Health/National Institute of General Medical Sciences to I.M.C. (GM088313), and a Research Scholar Grant to I.M.C. (121776) from the American Cancer Society.

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Correspondence to Kara L. McKinley or Iain M. Cheeseman.

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FURTHER INFORMATION

RCSB Protein Data Bank

3AN2

3VH5

Glossary

Meiotic drive

Preferential transmission of a genetic element during meiosis, such that it is represented in more than 50% of the gametes of a heterozygote.

Evolutionary new centromeres

(ENCs). Centromeres at a different site from the centromere of the chromosome ancestor, for which the movement of the centromere cannot be parsimoniously explained by a simple chromosome rearrangement.

Neocentromeres

Regions of chromosomes that have the functional characteristics of a centromere, but occur at a site distinct from the site of centromere formation for the chromosome in most organisms of the species, and lack canonical centromere DNA sequences.

Human artificial chromosomes

(HACs). Units of exogenous DNA that segregate autonomously in human cells.

Histone chaperone

A protein that binds to histones to facilitate nucleosome assembly.

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McKinley, K., Cheeseman, I. The molecular basis for centromere identity and function. Nat Rev Mol Cell Biol 17, 16–29 (2016). https://doi.org/10.1038/nrm.2015.5

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