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. Epub 2014 Feb 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Autoantigens / metabolism*
  • CCCTC-Binding Factor
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival
  • Centromere / metabolism*
  • Centromere Protein A
  • Chromatin / metabolism
  • Chromosomal Proteins, Non-Histone / metabolism*
  • Chromosome Mapping
  • DNA Damage
  • Epitopes / metabolism
  • Gene Expression Regulation, Neoplastic*
  • HeLa Cells
  • Histones / metabolism
  • Humans
  • Mass Spectrometry
  • Microscopy, Fluorescence
  • Molecular Chaperones / metabolism
  • Nuclear Proteins / metabolism*
  • Nucleosomes / metabolism
  • RNA, Small Interfering / metabolism
  • Repressor Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Autoantigens
  • CCCTC-Binding Factor
  • CENPA protein, human
  • CTCF protein, human
  • Centromere Protein A
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • DAXX protein, human
  • Epitopes
  • Histones
  • Molecular Chaperones
  • Nuclear Proteins
  • Nucleosomes
  • RNA, Small Interfering
  • Repressor Proteins

Associated data

  • GEO/GSE42951