Journal article
BET proteins promote efficient murine leukemia virus integration at transcription start sites
Proceedings of the National Academy of Sciences - PNAS, Vol.110(29), pp.12036-12041
07/16/2013
DOI: 10.1073/pnas.1307157110
PMCID: PMC3718171
PMID: 23818621
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.
Details
- Title: Subtitle
- BET proteins promote efficient murine leukemia virus integration at transcription start sites
- Creators
- Amit Sharma - College of Pharmacy, andRoss C Larue - College of Pharmacy, andMatthew R Plumb - College of Pharmacy, andNirav Malani - University of PennsylvaniaFrances Male - University of PennsylvaniaAlison Slaughter - College of Pharmacy, andJacques J Kessl - College of Pharmacy, andNikolozi Shkriabai - College of Pharmacy, andElizabeth Coward - University of PennsylvaniaSriram S Aiyer - University of Medicine and Dentistry of New JerseyPatrick L Green - The Ohio State UniversityLi Wu - The Ohio State UniversityMonica J Roth - University of Medicine and Dentistry of New JerseyFrederic D Bushman - University of PennsylvaniaMamuka Kvaratskhelia - College of Pharmacy, and
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.110(29), pp.12036-12041
- Publisher
- National Academy of Sciences
- DOI
- 10.1073/pnas.1307157110
- PMID
- 23818621
- PMCID
- PMC3718171
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Alternative title
- BET proteins are cofactors of MLV integrase
- Language
- English
- Date published
- 07/16/2013
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984001108802771
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