Journal article
IDR-targeting compounds suppress HPV genome replication via disruption of phospho-BRD4 association with DNA damage response factors
Molecular cell, Vol.84(2), pp.202-220.e15
01/18/2024
DOI: 10.1016/j.molcel.2023.11.022
PMCID: PMC10843765
PMID: 38103559
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.
Details
- Title: Subtitle
- IDR-targeting compounds suppress HPV genome replication via disruption of phospho-BRD4 association with DNA damage response factors
- Creators
- Shwu-Yuan WuHsien-Tsung Lai - The University of Texas Southwestern Medical CenterN Sanjib Banerjee - University of Alabama at BirminghamZonghui Ma - Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, TX 77555, USAJuan F Santana - University of IowaShuguang Wei - The University of Texas Southwestern Medical CenterXisheng Liu - University of Alabama at BirminghamMeirong Zhang - State Key Laboratory of Natural Medicines, Department of Organic Chemistry, China Pharmaceutical University, Nanjing 210009, P.R. ChinaJian Zhan - State Key Laboratory of Natural Medicines, Department of Organic Chemistry, China Pharmaceutical University, Nanjing 210009, P.R. ChinaHaiying Chen - Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, TX 77555, USABruce Posner - The University of Texas Southwestern Medical CenterYadong Chen - State Key Laboratory of Natural Medicines, Department of Organic Chemistry, China Pharmaceutical University, Nanjing 210009, P.R. ChinaDavid H Price - University of IowaLouise T Chow - University of Alabama at BirminghamJia Zhou - Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch (UTMB), Galveston, TX 77555, USA. Electronic address: jizhou@utmb.eduCheng-Ming Chiang
- Resource Type
- Journal article
- Publication Details
- Molecular cell, Vol.84(2), pp.202-220.e15
- DOI
- 10.1016/j.molcel.2023.11.022
- PMID
- 38103559
- PMCID
- PMC10843765
- NLM abbreviation
- Mol Cell
- eISSN
- 1097-4164
- Grant note
- R01 CA251698 / NCI NIH HHS
- Language
- English
- Electronic publication date
- 12/12/2023
- Date published
- 01/18/2024
- Academic Unit
- Biology; Biochemistry and Molecular Biology
- Record Identifier
- 9984531522302771
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