Cell Reports (Apr 2022)

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

  • Benjamin L. Allen,
  • Kim Quach,
  • Taylor Jones,
  • Cecilia B. Levandowski,
  • Christopher C. Ebmeier,
  • Jonathan D. Rubin,
  • Timothy Read,
  • Robin D. Dowell,
  • Alanna Schepartz,
  • Dylan J. Taatjes

Journal volume & issue
Vol. 39, no. 1
p. 110630

Abstract

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Summary: DNA-binding transcription factors (TFs) remain challenging to target with molecular probes. Many TFs function in part through interaction with Mediator, a 26-subunit complex that controls RNA polymerase II activity genome-wide. We sought to block p53 function by disrupting the p53-Mediator interaction. Through rational design and activity-based screening, we characterize a stapled peptide, with functional mimics of both p53 activation domains, that blocks p53-Mediator binding and selectively inhibits p53-dependent transcription in human cells; importantly, this “bivalent” peptide has negligible impact, genome-wide, on non-p53 target genes. Our proof-of-concept strategy circumvents the TF entirely and targets the TF-Mediator interface instead, with desired functional outcomes (i.e., selective inhibition of p53 activation). Furthermore, these results demonstrate that TF activation domains represent viable starting points for Mediator-targeting molecular probes, as an alternative to large compound libraries. Different TFs bind Mediator through different subunits, suggesting this strategy could be broadly applied to selectively alter gene expression programs.

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