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Histone deacetylase regulation of ATM-mediated DNA damage signaling

K Ted Thurn1, Scott Thomas, Paromita Raha

  • 1Corresponding Author: Pamela N. Munster, Division of Hematology and Oncology, Department of Medicine, University of California, 1600 Divisadero, Room A719, Box 1711, San Francisco, CA 94143. pmunster@medicine.ucsf.edu.

Molecular Cancer Therapeutics
|August 14, 2013
PubMed

Insights

Histone deacetylases (HDAC) regulate the DNA damage response by mitigating the Ataxia-telangiectasia mutated (ATM) pathway. Inhibiting HDACs decreases ATM activation, enhancing cancer cell sensitivity to genotoxic therapies.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • The Ataxia-telangiectasia mutated (ATM) pathway is crucial for DNA damage response, activating genes that promote cell-cycle arrest and repair.
  • Upregulation of ATM-responsive genes can lead to cancer cell resistance against genotoxic treatments.

Purpose of the Study:

  • To investigate the role of histone deacetylases (HDAC) in regulating the ATM pathway's response to DNA damage.
  • To explore the therapeutic potential of targeting HDACs in combination with genotoxic therapies.

Main Methods:

  • In vitro and in vivo experiments were conducted to assess the effects of HDAC inhibition on ATM pathway activation.
  • Specific depletion of HDAC1 and HDAC2 was performed to evaluate their individual contributions.

Main Results:

  • HDAC inhibition was found to decrease ATM activation and expression, as well as attenuate p53 activation.
  • Depletion of HDAC1 and HDAC2 modulated ATM activation, reduced induction of GADD45A and RRM2B, and increased sensitivity to DNA strand breaks.

Conclusions:

  • HDAC enzymes, particularly HDAC1 and HDAC2, play a significant role in the DNA damage response by regulating the ATM pathway.
  • The ATM pathway can serve as a pharmacodynamic marker for combination therapies involving HDAC inhibitors and genotoxic agents.

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