Histone deacetylase regulation of ATM-mediated DNA damage signaling.
Ataxia-telangiectasia mutated (ATM) is a major regulator of the DNA damage response. ATM promotes the activation of BRCA1, CHK2, and p53 leading to the induction of response genes such as CDKN1A (p21), GADD45A, and RRM2B that promote cell-cycle arrest and DNA repair. The upregulation of these response genes may contribute to resistance of cancer cells to genotoxic therapies. Here, we show that histone deacetylases (HDAC) play a major role in mitigating the response of the ATM pathway to DNA damage. HDAC inhibition decreased ATM activation and expression, and attenuated the activation of p53 in vitro and in vivo. Select depletion of HDAC1 and HDAC2 was sufficient to modulate ATM activation, reduce GADD45A and RRM2B induction, and increase sensitivity to DNA strand breaks. The regulation of ATM by HDAC enzymes therefore suggests a vital role for HDAC1 and HDAC2 in the DNA damage response, and the potential use of the ATM pathway as a pharmacodynamic marker for combination therapies involving HDAC inhibitors.
Corresponding 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.
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D064007:Ataxia Telangiectasia Mutated Proteins / Q000096:biosynthesis / Q000235:genetics*; D019313:BRCA1 Protein / Q000096:biosynthesis; D064447:Checkpoint Kinase 2 / Q000096:biosynthesis; D004249:DNA Damage / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2