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Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway

Yael Ziv1, Dana Bielopolski, Yaron Galanty

  • 1The David and Inez Myers Laboratory for Genetic Research, Department of Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. yaelz@post.tau.ac.il

Nature Cell Biology
|July 25, 2006
PubMed

Insights

DNA double-strand breaks trigger ATM-dependent chromatin relaxation. This process involves the protein KAP-1, identified as a key mediator in the DNA-damage response pathway.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • The cellular DNA-damage response (DDR) is crucial for maintaining genomic integrity.
  • Cytotoxic DNA lesions, particularly double-strand breaks (DSBs), activate complex signaling networks.
  • The role of DSB formation in chromatin condensation has been a long-standing question.

Purpose of the Study:

  • To investigate the impact of DSB formation on chromatin condensation.
  • To identify the molecular mediators of DSB-induced chromatin alterations.
  • To elucidate the role of ATM and KAP-1 in the DDR.

Main Methods:

  • Induction of DNA double-strand breaks in cellular models.
  • Assessment of chromatin condensation and relaxation using microscopy.
  • Analysis of protein phosphorylation, specifically ATM and KAP-1 (KRAB-associated protein 1).
  • Gene knockdown and site-directed mutagenesis to study protein function.

Main Results:

  • DSB formation leads to ATM-dependent chromatin relaxation.
  • ATM phosphorylates KAP-1 at Serine 824 at DNA damage sites, facilitating rapid chromatin spreading.
  • Ablation of KAP-1 phosphorylation prevents chromatin decondensation and increases sensitivity to DNA-damaging agents.
  • Constitutive KAP-1 phosphorylation results in sustained chromatin relaxation.

Conclusions:

  • Chromatin relaxation is a fundamental component of the DNA-damage response.
  • ATM and KAP-1 are identified as primary mediators of DSB-induced chromatin relaxation.
  • This pathway is critical for cellular response and survival following DNA damage.

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