Article ; Online: IDR-targeting compounds suppress HPV genome replication via disruption of phospho-BRD4 association with DNA damage response factors.
2023 Volume 84, Issue 2, Page(s) 202–220.e15
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 ... ...
| 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. |
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| MeSH term(s) | Humans ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Human Papillomavirus Viruses ; Papillomavirus Infections/drug therapy ; Papillomavirus Infections/genetics ; Proteomics ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Papillomaviridae/genetics ; Papillomaviridae/metabolism ; Viral Proteins/genetics ; Virus Replication/physiology ; DNA Repair ; Bromodomain Containing Proteins |
| Chemical Substances | Transcription Factors ; Nuclear Proteins ; Cell Cycle Proteins ; Viral Proteins ; BRD4 protein, human ; Bromodomain Containing Proteins |
| Language | English |
| Publishing date | 2023-12-15 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 1415236-8 |
| ISSN | 1097-4164 ; 1097-2765 |
| ISSN (online) | 1097-4164 |
| ISSN | 1097-2765 |
| DOI | 10.1016/j.molcel.2023.11.022 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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