Mislocalization of the Centromeric Histone Variant CenH3/CENP-A in Human Cells Depends on the Chaperone DAXX

Nicolas Lacoste, Adam Woolfe, Hiroaki Tachiwana, AnaVillar Garea, Teresa Barth, Sylvain Cantaloube, Hitoshi Kurumizaka, Axel Imhof, Geneviève Almouzni

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    126 Citations (Scopus)

    Abstract

    Centromeres are essential for ensuring proper chromosome segregation in eukaryotes. Their definition relies on the presence of a centromere-specific H3 histone variant CenH3, known as CENP-A in mammals. Its overexpression in aggressive cancers raises questions concerning its effect on chromatin dynamics and contribution to tumorigenesis. We find that CenH3 overexpression in human cells leads to ectopic enrichment at sites of active histone turnover involving a heterotypic tetramer containing CenH3-H4 with H3.3-H4. Ectopic localization of this particle depends on the H3.3 chaperone DAXX rather than the dedicated CenH3 chaperone HJURP. This aberrant nucleosome occludes CTCF binding and has a minor effect on gene expression. Cells overexpressing CenH3 are more tolerant of DNA damage. Both the survival advantage and CTCF occlusion in these cells are dependent on DAXX. Our findings illustrate how changes in histone variant levels can disrupt chromatin dynamics and suggests a possible mechanism for cell resistance to anticancer treatments.

    Original languageEnglish
    Pages (from-to)631-644
    Number of pages14
    JournalMolecular Cell
    Volume53
    Issue number4
    DOIs
    Publication statusPublished - 2014 Feb 20

    ASJC Scopus subject areas

    • Molecular Biology
    • Cell Biology

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    Lacoste, N., Woolfe, A., Tachiwana, H., Garea, A., Barth, T., Cantaloube, S., Kurumizaka, H., Imhof, A., & Almouzni, G. (2014). Mislocalization of the Centromeric Histone Variant CenH3/CENP-A in Human Cells Depends on the Chaperone DAXX. Molecular Cell, 53(4), 631-644. https://doi.org/10.1016/j.molcel.2014.01.018