Mislocalization of centromeric histone H3 variant CENP-A contributes to chromosomal instability (CIN) in human cells

Oncotarget. 2017 Jul 18;8(29):46781-46800. doi: 10.18632/oncotarget.18108.


Chromosomal instability (CIN) is a hallmark of many cancers and a major contributor to tumorigenesis. Centromere and kinetochore associated proteins such as the evolutionarily conserved centromeric histone H3 variant CENP-A, associate with centromeric DNA for centromere function and chromosomal stability. Stringent regulation of cellular CENP-A levels prevents its mislocalization in yeast and flies to maintain genome stability. CENP-A overexpression and mislocalization are observed in several cancers and reported to be associated with increased invasiveness and poor prognosis. We examined whether there is a direct relationship between mislocalization of overexpressed CENP-A and CIN using HeLa and chromosomally stable diploid RPE1 cell lines as model systems. Our results show that mislocalization of overexpressed CENP-A to chromosome arms leads to chromosome congression defects, lagging chromosomes, micronuclei formation and a delay in mitotic exit. CENP-A overexpressing cells showed altered localization of centromere and kinetochore associated proteins such as CENP-C, CENP-T and Nuf2 leading to weakened native kinetochores as shown by reduced interkinetochore distance and CIN. Importantly, our results show that mislocalization of CENP-A to chromosome arms is one of the major contributors for CIN as depletion of histone chaperone DAXX prevents CENP-A mislocalization and rescues the reduced interkinetochore distance and CIN phenotype in CENP-A overexpressing cells. In summary, our results establish that CENP-A overexpression and mislocalization result in a CIN phenotype in human cells. This study provides insights into how overexpression of CENP-A may contribute to CIN in cancers and underscore the importance of understanding the pathways that prevent CENP-A mislocalization for genome stability.

Keywords: CENP-A; Chromosome Section; DAXX; cancer; centromeres; chromosomal instability.

MeSH terms

  • Cell Line
  • Centromere / genetics*
  • Centromere / metabolism*
  • Centromere Protein A / genetics
  • Centromere Protein A / metabolism*
  • Chromosomal Instability*
  • Chromosome Segregation
  • Diploidy
  • Gene Expression
  • HeLa Cells
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Kinetochores / metabolism
  • Micronuclei, Chromosome-Defective
  • Models, Biological
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Phenotype
  • Protein Binding


  • Centromere Protein A
  • Histones