E6 oncoprotein represses p53-dependent gene activation via inhibition of protein acetylation independently of inducing p53 degradation.

The mechanism employed by DNA tumor viruses to inhibit p53-dependent transcription from chromatin is poorly understood. Here, we use in vitro-reconstituted chromatin and UV-irradiated cells to define the mechanism of human papillomavirus E6 oncoprotein in repressing p53-dependent transcription. We demonstrate that E6 does not prevent p53 or p300 recruitment to ...
the chromatin but inhibits p300-mediated acetylation on p53 and nucleosomal core histones. This suppression of protein acetylation requires the E6-interacting regions of p300. Moreover, E6 mutants unable to interact with p53 or p300, but not deficient in inducing p53 degradation, fail to inhibit p53-mediated activation, indicating that a p53-E6-p300-containing protein complex is critical for repressing p53-targeted gene activation. That E6 acts as a molecular switch converting p53-p300 from an activating complex to a repressing entity on the chromatin, which occurs independently of E6AP-mediated protein degradation pathway, may represent a general mechanism for gene regulation.
Mesh Terms:
Acetyl Coenzyme A, Acetylation, Acetyltransferases, Amino Acid Sequence, Animals, Cell Cycle Proteins, Cells, Cultured, Chromatin, Cyclin-Dependent Kinase Inhibitor p21, E1A-Associated p300 Protein, Histone Acetyltransferases, Histones, Humans, Macromolecular Substances, Mice, Mice, Knockout, Molecular Sequence Data, Nuclear Proteins, Oncogene Proteins, Viral, Proteasome Endopeptidase Complex, Repressor Proteins, Sequence Alignment, Trans-Activators, Transcription Factors, Transcription, Genetic, Transcriptional Activation, Tumor Suppressor Protein p53, p300-CBP Transcription Factors
Mol. Cell
Date: Jan. 21, 2005
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