RT Journal Article SR Electronic T1 The Wild-type and Gain-of-function Mutant p53 Enhance p300 Autoacetylation through Conformational Switching JF bioRxiv FD Cold Spring Harbor Laboratory SP 194704 DO 10.1101/194704 A1 Kaypee, Stephanie A1 Ghosh, Raka A1 Sahadevan, Smitha Asoka A1 Patil, Shilpa A1 Shasmal, Manidip A1 Ghosh, Piya A1 Roy, Neeladri A1 Sengupta, Jayati A1 Roy, Siddhartha A1 Kundu, Tapas K. YR 2018 UL http://biorxiv.org/content/early/2018/05/04/194704.abstract AB The transcriptional coactivator p300 is essential for p53 transactivation, although its precise mechanism remains unclear. We report that, p53 allosterically activates the acetyltransferase activity of p300 through the enhancement of p300 autoacetylation. Cryo-electron microscopy revealed that the domain organization of p300 is substantially altered upon binding of p53, suggesting that a structural switch may underpin the activation. Acetylated p300 accumulates near the transcription start sites accompanied by a similar enrichment of activating histone marks near those sites. Disruption of p53-p300 interaction by a site-directed peptide inhibitor abolished autoacetylated p300-mediated enhanced histone acetylation, suggesting a crucial role played by the allosteric activation in p53-mediated gene regulation. Gain-of-function mutant p53, known to impart aggressive proliferative properties in tumor cells, also activate p300 autoacetylation. The same peptide abolished many of the gain-of-functions of mutant p53 as well. We conclude that allosteric activation of p300 by p53 underpins gene regulation by p53. Reversal of gain-of-function properties of mutant p53 suggests that molecules targeting the p53-p300 interface may be good candidates for anti-tumor drugs.