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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Malani, Nirav Plumb, Matthew R. Slaughter, Alison Sharma, Amit Male, Frances Kvaratskhelia, Mamuka Coward, Elizabeth Aiyer, Sriram S. Roth, Monica J. Wu, Li Green, Patrick L. Shkriabai, Nikolozi Kessl, Jacques J. Larue, Ross C. Bushman, Frederic D. |
| Description | Author Affiliation: Sharma A ( Center for Retrovirus Research, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.); |
| Abstract | The selection of chromosomal targets for retroviral integration varies markedly, tracking with the genus of the retrovirus, suggestive of targeting by binding to cellular factors. γ-Retroviral murine leukemia virus (MLV) DNA integration into the host genome is favored at transcription start sites, but the underlying mechanism for this preference is unknown. Here, we have identified bromodomain and extraterminal domain (BET) proteins (Brd2, -3, -4) as cellular-binding partners of MLV integrase. We show that purified recombinant Brd4(1-720) binds with high affinity to MLV integrase and stimulates correct concerted integration in vitro. JQ-1, a small molecule that selectively inhibits interactions of BET proteins with modified histone sites impaired MLV but not HIV-1 integration in infected cells. Comparison of the distribution of BET protein-binding sites analyzed using ChIP-Seq data and MLV-integration sites revealed significant positive correlations. Antagonism of BET proteins, via JQ-1 treatment or RNA interference, reduced MLV-integration frequencies at transcription start sites. These findings elucidate the importance of BET proteins for MLV integration efficiency and targeting and provide a route to developing safer MLV-based vectors for human gene therapy. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 29 |
| Volume Number | 110 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2013-07-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Integrases Metabolism Leukemia Virus, Murine Enzymology Nuclear Proteins Recombinant Proteins Transcription Factors Transcription Initiation Site Physiology Virus Integration Animals Azepines Cell Line, Tumor Chromatin Immunoprecipitation HEK293 Cells High-Throughput Nucleotide Sequencing Host-Pathogen Interactions Mass Spectrometry Mice NIH 3T3 Cells Antagonists & Inhibitors Genetics Proteomics RNA Interference Triazoles Research Support, N.I.H., Extramural Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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