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Title: | Post-mitotic BET-induced reshaping of integrase quaternary structure supports wild-type MLV integration | Authors: | Borrenberghs, D. Zurnic, I. De Wit, F. Acke, A. Dirix, L. Cereseto, A. Debyser, Z. HENDRIX, Jelle |
Issue Date: | 2018 | Source: | NUCLEIC ACIDS RESEARCH, 47 (3), p. 1195-1210 | Abstract: | 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 Förster 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. | Notes: | Hendrix, J (reprint author), Katholieke Univ Leuven, Dept Chem, Lab Photochem & Spect, Celestijnenlaan 200F, B-3001 Leuven, Belgium. Hasselt Univ, Adv Opt Microscopy Ctr, Dynam Bioimaging Lab, Agoralaan C, B-3590 Diepenbeek, Belgium. Hasselt Univ, Biomed Res Inst BIOMED, Agoralaan C, B-3590 Diepenbeek, Belgium Debyser, Z (reprint author), Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Lab Mol Virol & Gene Therapy, Kapucijnenvoer 33, B-3001 Leuven, Flanders, Belgium. zeger.debyser@kuleuven.be; jelle.hendrix@uhasselt.be | Document URI: | http://hdl.handle.net/1942/27260 | ISSN: | 0305-1048 | e-ISSN: | 1362-4962 | DOI: | 10.1093/nar/gky1157 | ISI #: | 000467960500017 | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2020 |
Appears in Collections: | Research publications |
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gky1157.pdf | Published version | 2.71 MB | Adobe PDF | View/Open |
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