Abstract
Anumber of proteins are recruited to nuclear foci upon exposure to double-strand DNA damage, including 53BP1 and Rad51, but the precise role of these DNA damage-induced foci remain unclear. Here we show in a variety of human cell lines that histone deacetylase (HDAC) 4 is recruited to foci with kinetics similar to, and colocalizes with, 53BP1 after exposure to agents causing double-stranded DNA breaks. HDAC4 foci gradually disappeared in repair-proficient cells but persisted in repair-deficient cell lines or cells irradiated with a lethal dose, suggesting that resolution of HDAC4 foci is linked to repair. Silencing of HDAC4 via RNA interference surprisingly also decreased levels of 53BP1 protein, abrogated the DNA damage-induced G2 delay, and radiosensitized HeLa cells. Our combined results suggest that HDAC4 is a critical component of the DNA damage response pathway that acts through 53BP1 and perhaps contributes in maintaining the G2 cell cycle checkpoint.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Carrier Proteins / metabolism*
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Cell Line
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Cell Nucleus / radiation effects
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DNA Damage*
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DNA Repair
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Dose-Response Relationship, Radiation
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Etoposide / pharmacology
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G2 Phase
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Gamma Rays / adverse effects
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Histone Deacetylases / drug effects
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Histone Deacetylases / metabolism*
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Histone Deacetylases / radiation effects
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Humans
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Hydroxamic Acids / pharmacology
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Intracellular Signaling Peptides and Proteins*
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Kinetics
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Mutation
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Nucleic Acid Synthesis Inhibitors / pharmacology
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Phosphoproteins*
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Protein Synthesis Inhibitors / pharmacology
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RNA, Small Interfering / metabolism
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Repressor Proteins / drug effects
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Repressor Proteins / metabolism*
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Repressor Proteins / radiation effects
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Tumor Cells, Cultured
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Tumor Suppressor p53-Binding Protein 1
Substances
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Carrier Proteins
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DNA-Binding Proteins
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Hydroxamic Acids
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Intracellular Signaling Peptides and Proteins
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Nuclear Proteins
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Nucleic Acid Synthesis Inhibitors
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Phosphoproteins
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Protein Synthesis Inhibitors
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RNA, Small Interfering
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Repressor Proteins
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TP53BP1 protein, human
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Tumor Suppressor p53-Binding Protein 1
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trichostatin A
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Etoposide
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HDAC4 protein, human
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Histone Deacetylases