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Activation of ATM depends on chromatin interactions occurring before induction of DNA damage

Yong-Chul Kim1, Gabi Gerlitz, Takashi Furusawa

  • 1Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Nature Cell Biology
|December 17, 2008
PubMed

Insights

The nucleosome-binding protein HMGN1 optimizes the activation of ataxia-telangiectasia mutated (ATM) kinase following DNA double-stranded breaks (DSB). HMGN1 regulates ATM

Area of Science:

  • Molecular Biology
  • Genomics
  • Cellular Biology

Background:

  • Efficient DNA repair is vital for genomic stability and cancer prevention.
  • Double-stranded breaks (DSB) trigger chromatin alterations and activate ATM kinase.
  • The precise relationship between chromatin changes and ATM activation remains unclear.

Purpose of the Study:

  • To investigate the role of HMGN1 in modulating ATM activation after DSB.
  • To understand how HMGN1 influences ATM's interaction with chromatin.
  • To elucidate the link between HMGN1, histone modifications, and ATM signaling.

Main Methods:

  • Assessing ATM autophosphorylation and target activation after ionizing radiation (IR) in HMGN1-deficient cells.
  • Analyzing global histone H3K14 acetylation levels.
  • Evaluating the effect of histone deacetylase inhibitors on ATM activation.

Main Results:

  • HMGN1 is essential for optimal ATM activation following DSB.
  • Loss of HMGN1 or its chromatin-binding ability impairs IR-induced ATM autophosphorylation and target activation.
  • IR induces HMGN1-dependent global H3K14 acetylation.
  • Histone deacetylase inhibitors can restore efficient ATM activation in HMGN1-deficient cells.

Conclusions:

  • HMGN1 acts as a crucial mediator in ATM activation by regulating chromatin modifications.
  • HMGN1 influences the intranuclear organization of ATM, affecting its activation kinetics post-DNA damage.
  • This study reveals a direct link between HMGN1, histone acetylation, and the DNA damage response pathway.

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