HP1-beta mobilization promotes chromatin changes that initiate the DNA damage response

Nature. 2008 May 29;453(7195):682-6. doi: 10.1038/nature06875. Epub 2008 Apr 27.


Minutes after DNA damage, the variant histone H2AX is phosphorylated by protein kinases of the phosphoinositide kinase family, including ATM, ATR or DNA-PK. Phosphorylated (gamma)-H2AX-which recruits molecules that sense or signal the presence of DNA breaks, activating the response that leads to repair-is the earliest known marker of chromosomal DNA breakage. Here we identify a dynamic change in chromatin that promotes H2AX phosphorylation in mammalian cells. DNA breaks swiftly mobilize heterochromatin protein 1 (HP1)-beta (also called CBX1), a chromatin factor bound to histone H3 methylated on lysine 9 (H3K9me). Local changes in histone-tail modifications are not apparent. Instead, phosphorylation of HP1-beta on amino acid Thr 51 accompanies mobilization, releasing HP1-beta from chromatin by disrupting hydrogen bonds that fold its chromodomain around H3K9me. Inhibition of casein kinase 2 (CK2), an enzyme implicated in DNA damage sensing and repair, suppresses Thr 51 phosphorylation and HP1-beta mobilization in living cells. CK2 inhibition, or a constitutively chromatin-bound HP1-beta mutant, diminishes H2AX phosphorylation. Our findings reveal an unrecognized signalling cascade that helps to initiate the DNA damage response, altering chromatin by modifying a histone-code mediator protein, HP1, but not the code itself.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Casein Kinase II / antagonists & inhibitors
  • Casein Kinase II / metabolism
  • Chromatin / genetics
  • Chromatin / metabolism*
  • Chromobox Protein Homolog 5
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • DNA Damage*
  • Fibroblasts
  • Histones / metabolism
  • Humans
  • Hydrogen Bonding
  • Methylation
  • Mice
  • Mutation
  • Phosphorylation
  • Protein Binding
  • Protein Transport
  • Signal Transduction


  • CBX1 protein, human
  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • Histones
  • Chromobox Protein Homolog 5
  • Casein Kinase II