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bioRxiv · 10.1101/757401

Suppression of p53 response by targeting p53-Mediator binding with a stapled peptide

Allen, B. L.·Quach, K.·Levandowski, C. B.·Rubin, J. D.·Read, T.·Dowell, R. D.·Schepartz, A.·Taatjes, D. J.
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Abstract

DNA-binding transcription factors (TFs) remain challenging to target with molecular probes. Many TFs function in part through interaction with Mediator; we sought to block p53 function by disrupting the p53-Mediator interaction. Through rational design and activity-based screening, we characterized a stapled peptide, with functional mimics of both p53 activation domains, that selectively inhibited p53- and Mediator-dependent transcription in vitro. This \"bivalent peptide\" also suppressed p53 transcriptional response in human cancer cells. Our strategy circumvents the TF and instead targets the TF-Mediator interface, with desired transcriptional outcomes. Different TFs target Mediator through different subunits, suggesting this strategy could be broadly applied.

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Allen, B. L., Quach, K., Levandowski, C. B., Rubin, J. D., Read, T., Dowell, R. D., Schepartz, A., Taatjes, D. J.. 2019-09-04. Suppression of p53 response by targeting p53-Mediator binding with a stapled peptide. https://doi.org/10.1101/757401

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