Bromodomain and extraterminal inhibitors block the Epstein-Barr virus lytic cycle at two distinct steps
| Autor: | Kristin M. Keck, JJ L. Miranda, Samantha G. Fernandez, Stephanie M. Liu, Stephanie Moquin, Amanda He, Delsy M. Martinez, Jessica J. Somberg |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Herpesvirus 4 Human Cell Cycle Proteins medicine.disease_cause Biochemistry 0302 clinical medicine BET inhibitors Nuclear Proteins hemic and immune systems Acetylation Azepines Fanconi Anemia Complementation Group Proteins 3. Good health Chromatin Protein Transport Basic-Leucine Zipper Transcription Factors Lytic cycle 030220 oncology & carcinogenesis Host-Pathogen Interactions RNA Interference transcription Gene Expression Regulation Viral BRD4 bromodomain-containing protein 4 (BRD4) JQ1 Replication Origin Biology DNA replication Antiviral Agents Microbiology Virus Cell Line 03 medical and health sciences Viral Proteins herpesvirus medicine Humans Epstein-Barr virus Protein Interaction Domains and Motifs Molecular Biology Lysine Cell Biology Triazoles Virology Epstein–Barr virus Bromodomain BZLF1 030104 developmental biology Trans-Activators chromatin Virus Activation Protein Processing Post-Translational Transcription Factors Virus Physiological Phenomena |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X |
| Popis: | Lytic infection by the Epstein-Barr virus (EBV) poses numerous health risks, such as infectious mononucleosis and lymphoproliferative disorder. Proteins in the bromodomain and extraterminal (BET) family regulate multiple stages of viral life cycles and provide promising intervention targets. Synthetic small molecules can bind to the bromodomains and disrupt function by preventing recognition of acetylated lysine substrates. We demonstrate that JQ1 and other BET inhibitors block two different steps in the sequential cascade of the EBV lytic cycle. BET inhibitors prevent expression of the viral immediate-early protein BZLF1. JQ1 alters transcription of genes controlled by the host protein BACH1, and BACH1 knockdown reduces BZLF1 expression. BET proteins also localize to the lytic origin of replication (OriLyt) genetic elements, and BET inhibitors prevent viral late gene expression. There JQ1 reduces BRD4 recruitment during reactivation to preclude replication initiation. This represents a rarely observed dual mode of action for drugs. |
| Databáze: | OpenAIRE |
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