Journal
NUCLEIC ACIDS RESEARCH
Volume 47, Issue 3, Pages 1195-1210Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gky1157
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Funding
- FWO [G0B49.15]
- KU Leuven Research Council [OT] [OT/13/098]
- HIV-ERA EURECA [IWT-SBO-EURECA]
- KU Leuven IDO program [IDO/12/008]
- Belgian IAP Belvir
- Methusalem program [CASAS METH/08/04]
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The Moloney murine leukemia virus (MLV) is a prototype gammaretrovirus requiring nuclear disassembly before DNA integration. In the nucleus, integration site selection towards promoter/enhancer elements is mediated by the host factor bromo- and extraterminal domain (BET) proteins (bromodomain (Brd) proteins 2, 3 and 4). MLV-based retroviral vectors are used in gene therapy trials. In some trials leukemia occurred through integration of the MLV vector in close proximity to cellular oncogenes. BET-mediated integration is poorly understood and the nature of integrase oligomers heavily debated. Here, we created wild-type infectious MLV vectors natively incorporating fluorescent labeled IN and performed single-molecule intensity and Forster resonance energy transfer experiments. The nuclear localization of the MLV pre-integration complex neither altered the IN content, nor its quaternary structure. Instead, BET-mediated interaction of the MLV intasome with chromatin in the post-mitotic nucleus reshaped its quaternary structure.
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