2. Academic Validation
  3. Mislocalization of the centromeric histone variant CenH3/CENP-A in human cells depends on the chaperone DAXX

Mislocalization of the centromeric histone variant CenH3/CENP-A in human cells depends on the chaperone DAXX

  • Mol Cell. 2014 Feb 20;53(4):631-44. doi: 10.1016/j.molcel.2014.01.018.
Nicolas Lacoste 1,  Adam Woolfe 1,  Hiroaki Tachiwana 1,  Ana Villar Garea 2,  Teresa Barth 2,  Sylvain Cantaloube 1,  Hitoshi Kurumizaka 3,  Axel Imhof 2,  Geneviève Almouzni 4
Affiliations

Affiliations

  • 1 Institut Curie, Centre de Recherche, Paris75248, France; CNRS, UMR3664, Paris75248, France; Equipe Labellisée Ligue Contre le Cancer, UMR3664, Paris 75248, France; UPMC, UMR3664, Paris 75248, France.
  • 2 Histone Modifications Group, Scientific Coordinator ZfP (Zentrallabor für Proteinanalytik), Adolf Butenandt Institut, University of Munich, Schillerstraße 44, 80336 Munich, Germany.
  • 3 Laboratory of Structural Biology, Graduate School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan.
  • 4 Institut Curie, Centre de Recherche, Paris75248, France; CNRS, UMR3664, Paris75248, France; Equipe Labellisée Ligue Contre le Cancer, UMR3664, Paris 75248, France; UPMC, UMR3664, Paris 75248, France. Electronic address: genevieve.almouzni@curie.fr.
PMID: 24530302 DOI: 10.1016/j.molcel.2014.01.018
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.

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