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Histone H3 methylation links DNA damage detection to activation of the tumour suppressor Tip60

Yingli Sun1, Xiaofeng Jiang, Ye Xu

  • 1Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney St, Boston, MA 02115, USA.

Nature Cell Biology
|September 29, 2009
PubMed

Insights

Histone H3 trimethylated on lysine 9 (H3K9me3) at DNA double-strand breaks (DSBs) activates the tumor suppressor Tip60. This interaction is crucial for efficient DNA repair and preventing cancer.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Biology

Background:

  • DNA double-strand break (DSB) repair is essential for maintaining genomic stability.
  • Tip60, a tumor suppressor, is a critical acetyltransferase involved in DNA repair.
  • The mechanism by which DNA damage activates Tip60's acetyltransferase activity remains unknown.

Purpose of the Study:

  • To elucidate the mechanism of Tip60 activation following DNA damage.
  • To investigate the role of chromatin modifications in Tip60-mediated DNA repair.
  • To understand how Tip60's activity is regulated in response to DNA double-strand breaks.

Main Methods:

  • Investigated the interaction between Tip60 and histone modifications at DSBs.
  • Utilized depletion studies to assess the role of H3K9me3 and HP1beta.
  • Examined the involvement of the Mre11-Rad50-Nbs1 (MRN) complex in Tip60 activation.

Main Results:

  • Direct interaction between Tip60's chromodomain and H3K9me3 at DSBs activates Tip60's acetyltransferase activity.
  • Depletion of H3K9me3 impairs Tip60 activation, leading to defective ATM activation and DSB repair.
  • HP1beta displacement from H3K9me3 is necessary for Tip60 access, and the MRN complex targets Tip60 to H3K9me3.

Conclusions:

  • H3K9me3 plays a novel role in coordinating Tip60-dependent DNA repair activation.
  • Aberrant histone methylation patterns may contribute to cancer by affecting DSB repair efficiency.
  • This study reveals a new epigenetic mechanism regulating DNA repair pathways.

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