Molecular Cell
Volume 53, Issue 4, 20 February 2014, Pages 631-644
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Article
Mislocalization of the Centromeric Histone Variant CenH3/CENP-A in Human Cells Depends on the Chaperone DAXX

https://doi.org/10.1016/j.molcel.2014.01.018Get rights and content
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Highlights

  • Overexpression causes CenH3 mistargeting to ectopic sites of high histone turnover

  • Mislocalized CenH3 forms a heterotypic particle with H3.3 that can occlude CTCF

  • CenH3 mislocalization depends on the H3.3-specific histone chaperone DAXX

  • Ectopic CenH3 provides a DAXX-dependent cell-survival advantage upon DNA damage

Summary

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.

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These authors contributed equally to this work