Abstract
The tumor suppressor protein p53 regulates various cellular responses to DNA damage and plays a significant role in DNA repair. The nuclear p300/cyclic AMP-responsive element binding (CREB)-binding protein (CBP) proteins act as coactivators in supporting the transcription function of p53. We examined the role of the human homologue of yeast Rad23 protein A (hHR23A), one of the two human homologues of the Saccharomyces cerevisiae nucleotide excision repair gene product Rad23, in the p300/CBP-associated regulation of p53 activity. Overexpression of wild-type hHR23A inhibits the p53 transcriptional activity and results in a decreased steady-state protein level of cellular p53. The inhibitory effect of hHR23A can be overcome by the concomitant expression of p300, CBP, and p300 segments harboring C/H1 domain and neutralized by the coexpression of HIV accessory protein Vpr, which binds COOH terminus of hHR23A/B. Additionally, hHR23A was shown to interact in vitro and in vivo with p300 segments harboring C/H1 domain. These studies provide evidence for the involvement of hHR23A in the regulation of p53 activity through p300/CBP. Although the precise direct role of hHR23 proteins in regulation of p53 and DNA repair remains to be elucidated, our data suggest that the interaction between hHR23A and p300/CBP has important implications in cross-talk between the p53 pathway and DNA repair.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cyclic AMP Response Element-Binding Protein / biosynthesis
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Cyclic AMP Response Element-Binding Protein / metabolism
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Cyclic AMP Response Element-Binding Protein / physiology*
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / biosynthesis
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DNA Repair Enzymes
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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Down-Regulation / physiology
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E1A-Associated p300 Protein
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Gene Expression Regulation / physiology
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Humans
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Mice
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Nuclear Proteins / biosynthesis
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Nuclear Proteins / metabolism
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Nuclear Proteins / physiology*
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Protein Binding
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-mdm2
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Trans-Activators / biosynthesis
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Trans-Activators / metabolism
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Trans-Activators / physiology*
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Transcription, Genetic / physiology*
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Transcriptional Activation / physiology
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Tumor Suppressor Protein p53 / antagonists & inhibitors
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Protein p53 / physiology*
Substances
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CDKN1A protein, human
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Cdkn1a protein, mouse
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Cyclic AMP Response Element-Binding Protein
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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DNA-Binding Proteins
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Nuclear Proteins
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Proto-Oncogene Proteins
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Trans-Activators
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Tumor Suppressor Protein p53
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RAD23A protein, human
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E1A-Associated p300 Protein
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Ep300 protein, mouse
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MDM2 protein, human
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Mdm2 protein, mouse
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Proto-Oncogene Proteins c-mdm2
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DNA Repair Enzymes