Role for hACF1 in the G2/M damage checkpoint

Nucleic Acids Res. 2011 Oct;39(19):8445-56. doi: 10.1093/nar/gkr435. Epub 2011 Jul 11.

Abstract

Active chromatin remodelling is integral to the DNA damage response in eukaryotes, as damage sensors, signalling molecules and repair enzymes gain access to lesions. A variety of nucleosome remodelling complexes is known to promote different stages of DNA repair. The nucleosome sliding factors CHRAC/ACF of Drosophila are involved in chromatin organization during development. Involvement of corresponding hACF1-containing mammalian nucleosome sliding factors in replication, transcription and very recently also non-homologous end-joining of DNA breaks have been suggested. We now found that hACF1-containing factors are more generally involved in the DNA damage response. hACF1 depletion increases apoptosis, sensitivity to radiation and compromises the G2/M arrest that is activated in response to UV- and X-rays. In the absence of hACF1, γH2AX and CHK2ph signals are diminished. hACF1 and its ATPase partner SNF2H rapidly accumulate at sites of laser-induced DNA damage. hACF1 is also required for a tight checkpoint that is induced upon replication fork collapse. ACF1-depleted cells that are challenged with aphidicolin enter mitosis despite persistence of lesions and accumulate breaks in metaphase chromosomes. hACF1-containing remodellers emerge as global facilitators of the cellular response to a variety of different types of DNA damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aphidicolin / toxicity
  • Apoptosis
  • Cell Line
  • Chromosomal Proteins, Non-Histone
  • Chromosome Fragility
  • DNA Damage*
  • DNA Repair*
  • G2 Phase Cell Cycle Checkpoints*
  • Humans
  • M Phase Cell Cycle Checkpoints*
  • RNA Interference
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / physiology*

Substances

  • BAZ1A protein, human
  • Chromosomal Proteins, Non-Histone
  • Transcription Factors
  • Aphidicolin