IDR-targeting compounds suppress HPV genome replication via disruption of phospho-BRD4 association with DNA damage response factors

Shwu Yuan Wu, Hsien Tsung Lai, N. Sanjib Banerjee, Zonghui Ma, Juan F. Santana, Shuguang Wei, Xisheng Liu, Meirong Zhang, Jian Zhan, Haiying Chen, Bruce Posner, Yadong Chen, David H. Price, Louise T. Chow, Jia Zhou, Cheng Ming Chiang

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Compounds binding to the bromodomains of bromodomain and extra-terminal (BET) family proteins, particularly BRD4, are promising anticancer agents. Nevertheless, side effects and drug resistance pose significant obstacles in BET-based therapeutics development. Using high-throughput screening of a 200,000-compound library, we identified small molecules targeting a phosphorylated intrinsically disordered region (IDR) of BRD4 that inhibit phospho-BRD4 (pBRD4)-dependent human papillomavirus (HPV) genome replication in HPV-containing keratinocytes. Proteomic profiling identified two DNA damage response factors—53BP1 and BARD1—crucial for differentiation-associated HPV genome amplification. pBRD4-mediated recruitment of 53BP1 and BARD1 to the HPV origin of replication occurs in a spatiotemporal and BRD4 long (BRD4-L) and short (BRD4-S) isoform-specific manner. This recruitment is disrupted by phospho-IDR-targeting compounds with little perturbation of the global transcriptome and BRD4 chromatin landscape. The discovery of these protein-protein interaction inhibitors (PPIi) not only demonstrates the feasibility of developing PPIi against phospho-IDRs but also uncovers antiviral agents targeting an epigenetic regulator essential for virus-host interaction and cancer development.

Original languageEnglish (US)
Pages (from-to)202-220.e15
JournalMolecular cell
Volume84
Issue number2
DOIs
StatePublished - Jan 18 2024

Keywords

  • 53BP1
  • antiviral
  • BARD1
  • BET
  • BRD4
  • compound
  • DDR
  • HPV
  • IDR
  • PPI inhibitors

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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