The Flexible Ends of CENP-A Nucleosome Are Required for Mitotic Fidelity

Yohan Roulland, Khalid Ouararhni, Mladen Naidenov, Lorrie Ramos, Muhammad Shuaib, Sajad Hussain Syed, Imtiaz Nizar Lone, Ramachandran Boopathi, Emeline Fontaine, Gabor Papai, Hiroaki Tachiwana, Thierry Gautier, Dimitrios Skoufias, Kiran Padmanabhan, Jan Bednar, Hitoshi Kurumizaka, Patrick Schultz, Dimitar Angelov, Ali Hamiche, Stefan Dimitrov

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Abstract

CENP-A is a histone variant, which replaces histone H3 at centromeres and confers unique properties to centromeric chromatin. The crystal structure of CENP-A nucleosome suggests flexible nucleosomal DNA ends, but their dynamics in solution remains elusive and their implication in centromere function is unknown. Using electron cryo-microscopy, we determined the dynamic solution properties of the CENP-A nucleosome. Our biochemical, proteomic, and genetic data reveal that higher flexibility of DNA ends impairs histone H1 binding to the CENP-A nucleosome. Substituting the 2-turn αN-helix of CENP-A with the 3-turn αN-helix of H3 results in compact particles with rigidified DNA ends, able to bind histone H1. In vivo replacement of CENP-A with H3-CENP-A hybrid nucleosomes leads to H1 recruitment, delocalization of kinetochore proteins, and significant mitotic and cytokinesis defects. Our data reveal that the evolutionarily conserved flexible ends of the CENP-A nucleosomes are essential to ensure the fidelity of the mitotic pathway.

Original languageEnglish
Pages (from-to)674-685
Number of pages12
JournalMolecular Cell
Volume63
Issue number4
DOIs
Publication statusPublished - 18 Aug 2016
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Roulland, Y., Ouararhni, K., Naidenov, M., Ramos, L., Shuaib, M., Syed, S. H., Lone, I. N., Boopathi, R., Fontaine, E., Papai, G., Tachiwana, H., Gautier, T., Skoufias, D., Padmanabhan, K., Bednar, J., Kurumizaka, H., Schultz, P., Angelov, D., Hamiche, A., & Dimitrov, S. (2016). The Flexible Ends of CENP-A Nucleosome Are Required for Mitotic Fidelity. Molecular Cell, 63(4), 674-685. https://doi.org/10.1016/j.molcel.2016.06.023