Abstract
Cells are frequently challenged by DNA double-strand breaks (DSB) that threaten their normal function and survival. In mammalian cells, the repair of DSBs is predominantly mediated by the DNA-dependent protein kinase (DNA-PK) complex. We unexpectedly found that the corepressor silencing mediator for retinoid and thyroid hormone receptor (SMRT) associates with the DNA-PK repair complex. The SMRT/histone deacetylase 3 complex is required for the transcriptional repressive property of the Ku70 subunit of the repair complex. Moreover, SMRT, but not the related Nuclear Receptor Corepressor, is required for cellular recovery from DNA DSBs induced by ionizing radiation or DNA damage-inducing drugs. Thus, the corepressor SMRT plays a novel and critical role in the cellular response to DSBs.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Antigens, Nuclear / metabolism
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DNA Damage
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DNA Repair / physiology*
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DNA-Activated Protein Kinase / metabolism
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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HeLa Cells
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Histone Deacetylases / metabolism
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Humans
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Ku Autoantigen
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Nuclear Receptor Co-Repressor 1
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Nuclear Receptor Co-Repressor 2
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RNA, Small Interfering / genetics
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Repressor Proteins / antagonists & inhibitors
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Repressor Proteins / physiology*
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Substrate Specificity
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Transcriptional Activation
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Transfection
Substances
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Antigens, Nuclear
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DNA-Binding Proteins
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NCOR1 protein, human
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NCOR2 protein, human
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Nuclear Proteins
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Nuclear Receptor Co-Repressor 1
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Nuclear Receptor Co-Repressor 2
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RNA, Small Interfering
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Repressor Proteins
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DNA-Activated Protein Kinase
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Histone Deacetylases
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histone deacetylase 3
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Xrcc6 protein, human
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Ku Autoantigen