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The ACF1 complex is required for DNA double-strand break repair in human cells

Li Lan1, Ayako Ui, Satoshi Nakajima

  • 1Department of Molecular Genetics, Institute of Development, Aging and Cancer, Tohoku University, Seiryomachi 4-1, Sendai 980-8575, Japan.

Molecular Cell
|December 22, 2010
PubMed

Insights

Chromatin remodelers ACF1 and SNF2H are crucial for DNA double-strand break (DSB) repair in human cells. Suppressing these factors impairs nonhomologous end-joining and homologous recombination, leading to unrepaired DSBs and increased sensitivity to DNA-damaging agents.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • DNA double-strand breaks (DSBs) are critical DNA lesions repaired by nonhomologous end-joining (NHEJ) or homologous recombination (HR).
  • The precise cellular mechanisms governing DSB repair pathways remain incompletely understood.
  • Chromatin remodeling plays a vital role in DNA repair, but specific factors involved are still being elucidated.

Purpose of the Study:

  • To investigate the role of ATP-dependent chromatin-remodeling factors ACF1 and SNF2H in DNA double-strand break repair.
  • To determine the impact of ACF1 and SNF2H on NHEJ and HR pathways.
  • To elucidate the interaction of these remodelers with key DSB repair proteins.

Main Methods:

  • Utilized human cell lines to study DNA double-strand break repair mechanisms.
  • Employed techniques to suppress the expression of ACF1 and SNF2H.
  • Assessed cellular sensitivity to X-rays and chemical DSB-inducing agents.
  • Investigated protein-protein interactions using co-immunoprecipitation and proximity assays.
  • Quantified the frequency of NHEJ and HR in depleted cells.

Main Results:

  • ACF1 and SNF2H rapidly accumulate at sites of DNA double-strand breaks.
  • Suppression of ACF1 or SNF2H leads to extreme sensitivity to DSB-inducing agents and unrepaired DSBs.
  • ACF1 directly interacts with KU70, facilitating KU protein accumulation at DSBs.
  • The KU70/80 complex associates with the CHRAC complex (containing ACF1, SNF2H) post-DSB induction.
  • Depletion of ACF1 or SNF2H significantly reduces the frequency of both NHEJ and HR.

Conclusions:

  • ACF1 and SNF2H are essential ATP-dependent chromatin remodelers required for efficient DNA double-strand break repair in human cells.
  • These factors are critical for the proper functioning of both NHEJ and HR pathways.
  • ACF1 and its associated complexes, including SNF2H, play a significant role in orchestrating DSB repair processes through chromatin remodeling and interaction with repair machinery.

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