Title: The BET Family of proteins targets moloney murine leukemia virus integration near transcription start sites
Authors: De Rijck, Jan *
de Kogel, Christine *
Demeulemeester, Jonas
Vets, Sofie
Elashkar, Sara
Malani, Nirav
Bushman, Frederic D
Landuyt, Bart
Husson, Steven J
Busschots, Katrien
Gijsbers, Rik #
Debyser, Zeger # ×
Issue Date: Nov-2013
Publisher: Elsevier Inc
Series Title: Cell reports vol:5 issue:4 pages:886-894
Article number: S2211-1247(13)00563-9
Abstract: A hallmark of retroviral replication is integration of the viral genome into host cell DNA. This characteristic makes retrovirus-based vectors attractive delivery vehicles for gene therapy. However, adverse events in gene therapeutic trials, caused by activation of proto-oncogenes due to murine leukemia virus (MLV)-derived vector integration, hamper their application. Here, we show that bromodomain and extraterminal (BET) proteins (BRD2, BRD3, and BRD4) and MLV integrase specifically interact and colocalize within the nucleus of the cell. Inhibition of the BET proteins' chromatin interaction via specific bromodomain inhibitors blocks MLV virus replication at the integration step. MLV integration site distribution parallels the chromatin binding profile of BET proteins, and expression of an artificial fusion protein of the BET integrase binding domain with the chromatin interaction domain of the lentiviral targeting factor LEDGF/p75 retargets MLV integration away from transcription start sites and into the body of actively transcribed genes, conforming to the HIV integration pattern. Together, these data validate BET proteins as MLV integration targeting factors.
ISSN: 2211-1247
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Virology and Gene Therapy
* (joint) first author
× corresponding author
# (joint) last author

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