Abstract
In response to DNA damage, mammalian cells trigger the p53-dependent transcriptional induction of factors that regulate DNA repair, cell-cycle progression, or cell survival. Through differential proteomics, we identify heterogeneous nuclear ribonucleoprotein K (hnRNP K) as being rapidly induced by DNA damage in a manner that requires the DNA-damage signaling kinases ATM or ATR. Induction of hnRNP K ensues through the inhibition of its ubiquitin-dependent proteasomal degradation mediated by the ubiquitin E3 ligase HDM2/MDM2. Strikingly, hnRNP K depletion abrogates transcriptional induction of p53 target genes and causes defects in DNA-damage-induced cell-cycle-checkpoint arrests. Furthermore, in response to DNA damage, p53 and hnRNP K are recruited to the promoters of p53-responsive genes in a mutually dependent manner. These findings establish hnRNP K as a new HDM2 target and show that, by serving as a cofactor for p53, hnRNP K plays key roles in coordinating transcriptional responses to DNA damage.
Publication types
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Research Support, Non-U.S. Gov't
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Retracted Publication
MeSH terms
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Animals
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle / genetics
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Cell Cycle / physiology
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line
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Cell Line, Tumor
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cysteine Proteinase Inhibitors / pharmacology
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DNA Damage / physiology*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Gene Expression / drug effects
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Gene Expression / radiation effects
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Heterogeneous-Nuclear Ribonucleoprotein K / genetics
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Heterogeneous-Nuclear Ribonucleoprotein K / metabolism
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Heterogeneous-Nuclear Ribonucleoprotein K / physiology*
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Humans
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Leupeptins / pharmacology
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Morpholines / pharmacology
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Phleomycins / pharmacology
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Promoter Regions, Genetic / genetics
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Proteasome Endopeptidase Complex / metabolism
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Proteasome Inhibitors
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Protein Binding
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Protein Kinase Inhibitors / pharmacology
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-mdm2 / genetics
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Proto-Oncogene Proteins c-mdm2 / metabolism*
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Pyrones / pharmacology
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Radiation, Ionizing
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Ribonucleoproteins / genetics
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Ribonucleoproteins / metabolism
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Ribonucleoproteins / physiology
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Transcription, Genetic / genetics
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Transfection
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Ubiquitin / metabolism
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Ultraviolet Rays
Substances
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2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one
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CDKN1A protein, human
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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Cysteine Proteinase Inhibitors
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DNA-Binding Proteins
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Heterogeneous-Nuclear Ribonucleoprotein K
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Leupeptins
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Morpholines
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Phleomycins
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Proteasome Inhibitors
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Protein Kinase Inhibitors
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Pyrones
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RNA, Small Interfering
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Ribonucleoproteins
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Ubiquitin
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HNRNPK protein, human
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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ATM protein, human
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases
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Proteasome Endopeptidase Complex
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde