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PLoS Pathog. 2009 Jul;5(7):e1000522. doi: 10.1371/journal.ppat.1000522. Epub 2009 Jul 17.

LEDGF/p75 proteins with alternative chromatin tethers are functional HIV-1 cofactors.

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1
Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.

Abstract

LEDGF/p75 can tether over-expressed lentiviral integrase proteins to chromatin but how this underlies its integration cofactor role for these retroviruses is unclear. While a single integrase binding domain (IBD) binds integrase, a complex N-terminal domain ensemble (NDE) interacts with unknown chromatin ligands. Whether integration requires chromatin tethering per se, specific NDE-chromatin ligand interactions or other emergent properties of LEDGF/p75 has been elusive. Here we replaced the NDE with strongly divergent chromatin-binding modules. The chimeras rescued integrase tethering and HIV-1 integration in LEDGF/p75-deficient cells. Furthermore, chromatin ligands could reside inside or outside the nucleosome core, and could be protein or DNA. Remarkably, a short Kaposi's sarcoma virus peptide that binds the histone 2A/B dimer converted GFP-IBD from an integration blocker to an integration cofactor that rescues over two logs of infectivity. NDE mutants were corroborative. Chromatin tethering per se is a basic HIV-1 requirement and this rather than engagement of particular chromatin ligands is important for the LEDGF/p75 cofactor mechanism.

PMID:
19609362
PMCID:
PMC2706977
DOI:
10.1371/journal.ppat.1000522
[Indexed for MEDLINE]
Free PMC Article

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