Replication Stress Shapes a Protective Chromatin Environment across Fragile Genomic Regions

Mol Cell. 2018 Jan 4;69(1):36-47.e7. doi: 10.1016/j.molcel.2017.11.021. Epub 2017 Dec 14.


Recent integrative epigenome analyses highlight the importance of functionally distinct chromatin states for accurate cell function. How these states are established and maintained is a matter of intense investigation. Here, we present evidence for DNA damage as an unexpected means to shape a protective chromatin environment at regions of recurrent replication stress (RS). Upon aberrant fork stalling, DNA damage signaling and concomitant H2AX phosphorylation coordinate the FACT-dependent deposition of macroH2A1.2, a histone variant that promotes DNA repair by homologous recombination (HR). MacroH2A1.2, in turn, facilitates the accumulation of the tumor suppressor and HR effector BRCA1 at replication forks to protect from RS-induced DNA damage. Consequently, replicating primary cells steadily accrue macroH2A1.2 at fragile regions, whereas macroH2A1.2 loss in these cells triggers DNA damage signaling-dependent senescence, a hallmark of RS. Altogether, our findings demonstrate that recurrent DNA damage contributes to the chromatin landscape to ensure the epigenomic integrity of dividing cells.

Keywords: DNA repair; FACT; chromatin; macro-histone; macroH2A1.2; replication stress; senescence.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • BRCA1 Protein / metabolism
  • Carcinogenesis / genetics*
  • Cell Division / genetics
  • Cells, Cultured
  • Cellular Senescence / genetics
  • Chromatin / genetics*
  • DNA Damage / genetics*
  • DNA Repair / genetics*
  • DNA Replication / genetics*
  • Genomic Instability / physiology
  • Histones / genetics*
  • Homologous Recombination / genetics*
  • Humans
  • Signal Transduction / genetics


  • BRCA1 Protein
  • BRCA1 protein, human
  • Chromatin
  • Histones
  • macroH2A histone