CDK1-mediated phosphorylation at H2B serine 6 is required for mitotic chromosome segregation

J Cell Biol. 2019 Apr 1;218(4):1164-1181. doi: 10.1083/jcb.201806057. Epub 2019 Feb 14.

Abstract

Faithful mitotic chromosome segregation is required for the maintenance of genomic stability. We discovered the phosphorylation of histone H2B at serine 6 (H2B S6ph) as a new chromatin modification site and found that this modification occurs during the early mitotic phases at inner centromeres and pericentromeric heterochromatin. This modification is directly mediated by cyclin B1-associated CDK1, and indirectly by Aurora B, and is antagonized by PP1-mediated dephosphorylation. H2B S6ph impairs chromatin binding of the histone chaperone SET (I2PP2A), which is important for mitotic fidelity. Injection of phosphorylation-specific H2B S6 antibodies in mitotic cells caused anaphase defects with impaired chromosome segregation and incomplete cytokinesis. As H2B S6ph is important for faithful chromosome separation, this modification may contribute to the prevention chromosomal instability and aneuploidy which frequently occur in cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CDC2 Protein Kinase / genetics
  • CDC2 Protein Kinase / metabolism*
  • Cell Nucleus / enzymology*
  • Cell Nucleus / genetics
  • Chromosome Segregation*
  • Chromosomes, Human*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Female
  • Genomic Instability
  • HCT116 Cells
  • HEK293 Cells
  • HeLa Cells
  • Histone Chaperones / genetics
  • Histone Chaperones / metabolism
  • Histones / metabolism*
  • Humans
  • Mitosis*
  • Neoplasms / enzymology
  • Neoplasms / genetics
  • Phosphorylation
  • Protein Binding
  • Retinal Pigment Epithelium / enzymology
  • Serine
  • Signal Transduction

Substances

  • DNA-Binding Proteins
  • Histone Chaperones
  • Histones
  • SET protein, human
  • Serine
  • CDC2 Protein Kinase
  • CDK1 protein, human