| Literature DB >> 24183673 |
Jan De Rijck1, Christine de Kogel, Jonas Demeulemeester, Sofie Vets, Sara El Ashkar, Nirav Malani, Frederic D Bushman, Bart Landuyt, Steven J Husson, Katrien Busschots, Rik Gijsbers, Zeger Debyser.
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.Entities:
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Year: 2013 PMID： 24183673 PMCID： PMC4197836 DOI： 10.1016/j.celrep.2013.09.040
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423