Abstract
Histone acetyltransferases (HATs) regulate transcription, chromatin structure and DNA repair. Here, we utilized a novel HAT inhibitor, anacardic acid, to examine the role of HATs in the DNA damage response. Anacardic acid inhibits the Tip60 HAT in vitro, and blocks the Tip60-dependent activation of the ATM and DNA-PKcs protein kinases by DNA damage in vivo. Further, anacardic acid sensitizes human tumor cells to the cytotoxic effects of ionizing radiation. These results demonstrate a central role for HATs such as Tip60 in regulating the DNA damage response. HAT inhibitors provide a novel therapeutic approach for increasing the sensitivity of tumors to radiation therapy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Anacardic Acids / pharmacology
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Anacardic Acids / therapeutic use*
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Line, Tumor
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DNA-Activated Protein Kinase / antagonists & inhibitors
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DNA-Binding Proteins / antagonists & inhibitors
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use
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HeLa Cells
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Histone Acetyltransferases / antagonists & inhibitors*
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Humans
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Lysine Acetyltransferase 5
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Neoplasms / radiotherapy*
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Radiation, Ionizing*
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Radiation-Sensitizing Agents*
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Tumor Suppressor Proteins / antagonists & inhibitors
Substances
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Anacardic Acids
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Cell Cycle Proteins
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DNA-Binding Proteins
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Enzyme Inhibitors
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Radiation-Sensitizing Agents
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Tumor Suppressor Proteins
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anacardic acid
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Histone Acetyltransferases
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KAT5 protein, human
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Lysine Acetyltransferase 5
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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DNA-Activated Protein Kinase
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Protein Serine-Threonine Kinases