title: Mislocalization of the centromeric histone variant CenH3/CENP-A in human cells depends on the chaperone DAXX.
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.
authors: 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.
authors: Nicolas
authors: N
authors: Lacoste
authors: 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.
authors: Adam
authors: A
authors: Woolfe
authors: 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.
authors: Hiroaki
authors: H
authors: Tachiwana
authors: Histone Modifications Group, Scientific Coordinator ZfP (Zentrallabor für Proteinanalytik), Adolf Butenandt Institut, University of Munich, Schillerstraße 44, 80336 Munich, Germany.
authors: Ana Villar
authors: AV
authors: Garea
authors: Histone Modifications Group, Scientific Coordinator ZfP (Zentrallabor für Proteinanalytik), Adolf Butenandt Institut, University of Munich, Schillerstraße 44, 80336 Munich, Germany.
authors: Teresa
authors: T
authors: Barth
authors: 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.
authors: Sylvain
authors: S
authors: Cantaloube
authors: Laboratory of Structural Biology, Graduate School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan.
authors: Hitoshi
authors: H
authors: Kurumizaka
authors: Histone Modifications Group, Scientific Coordinator ZfP (Zentrallabor für Proteinanalytik), Adolf Butenandt Institut, University of Munich, Schillerstraße 44, 80336 Munich, Germany.
authors: Axel
authors: A
authors: Imhof
authors: 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.
authors: Geneviève
authors: G
authors: Almouzni
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D001324:Autoantigens / Q000378:metabolism*; D000076246:CCCTC-Binding Factor; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D002503:Centromere / Q000378:metabolism*; D000076247:Centromere Protein A; D002843:Chromatin / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D002874:Chromosome Mapping; D056970:Co-Repressor Proteins; D004249:DNA Damage; D000939:Epitopes / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D013058:Mass Spectrometry; D008856:Microscopy, Fluorescence; D018832:Molecular Chaperones / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D009707:Nucleosomes / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001324:Autoantigens; D000076246:CCCTC-Binding Factor; C000619700:CENPA protein, human; C000619697:CTCF protein, human; D000076247:Centromere Protein A; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D000939:Epitopes; D006657:Histones; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D009707:Nucleosomes; D034741:RNA, Small Interfering; D012097:Repressor Proteins