RT Journal Article
SR Electronic
T1 Suppression of p53 response by targeting p53-Mediator binding with a stapled peptide
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 757401
DO 10.1101/757401
A1 BL Allen
A1 K Quach
A1 CB Levandowski
A1 JD Rubin
A1 T Read
A1 RD Dowell
A1 A Schepartz
A1 DJ Taatjes
YR 2019
UL http://biorxiv.org/content/early/2019/09/04/757401.abstract
AB 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.