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BRD4 Phosphorylation Regulates HPV E2-Mediated Viral Transcription, Origin Replication, and Cellular MMP-9 Expression
Shwu-Yuan Wu1, Dawn Sijin Nin2, A-Young Lee3
1Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Cell Reports
|August 2, 2016
Summary
Bromodomain-containing protein 4 (BRD4) uses a phosphorylation-induced switch to recruit human papillomavirus (HPV) E2 protein and activate gene expression. This mechanism is crucial for viral DNA replication and cellular matrix metalloproteinase-9 (MMP-9) promoter activity.
Area of Science:
- Molecular Biology
- Epigenetics
- Virology
Background:
- Post-translational modifications regulate protein function and interactions.
- Bromodomain-containing protein 4 (BRD4) is a key transcription co-factor and chromatin regulator.
- Human papillomavirus (HPV) infection is associated with cancer and relies on viral proteins for replication and gene expression.
Purpose of the Study:
- To elucidate the mechanism by which BRD4 interacts with HPV E2 protein.
- To investigate the role of BRD4 phosphorylation in viral gene regulation and DNA replication.
- To identify potential therapeutic targets for HPV-associated diseases.
Main Methods:
- Investigated BRD4 phosphorylation-induced switch mechanism.
- Analyzed recruitment of HPV E2 protein to viral and cellular promoters.
- Studied the impact on matrix metalloproteinase-9 (MMP-9) expression and keratinocyte differentiation.
- Assessed BRD4's role in HPV DNA replication.
- Screened compounds targeting phospho-BRD4.
Main Results:
- BRD4 phosphorylation triggers a switch mechanism to recruit HPV E2 protein.
- This recruitment enhances expression of viral early genes and cellular MMP-9.
- BRD4 phosphorylation is essential for E2- and origin-dependent HPV DNA replication.
- Specific compounds targeting phospho-BRD4 inhibit these functions.
Conclusions:
- BRD4 phosphorylation is a critical regulator of HPV transcription and replication.
- The identified phospho-BRD4 targeting compounds offer a potential therapeutic strategy.
- Understanding BRD4's role in HPV infection opens new avenues for treatment.
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