Lens epithelium-derived growth factor fusion proteins redirect HIV-1 DNA integration.

Journal article

Lens epithelium-derived growth factor (LEDGF) fusion proteins can direct HIV-1 DNA integration to novel sites in the host genome. The C terminus of LEDGF contains an integrase binding domain (IBD), and the N terminus binds chromatin. LEDGF normally directs integrations to the bodies of expressed genes. Replacing the N terminus of LEDGF with chromatin binding domains (CBDs) from other proteins changes the specificity of HIV-1 DNA integration. We chose two well-characterized CBDs: the plant homeodomain (PHD) finger from ING2 and the chromodomain from heterochromatin binding protein 1alpha (HP1alpha). The ING2 PHD finger binds H3K4me3, a histone mark that is associated with the transcriptional start sites of expressed genes. The HP1alpha chromodomain binds H3K9me2,3, histone marks that are widely distributed throughout the genome. A fusion protein in which the ING2 PHD finger was linked to the LEDGF IBD directed integrations near the start sites of expressed genes. A similar fusion protein in which the HP1alpha chromodomain was linked to the LEDGF IBD directed integrations to sites that differed from both the PHD finger fusion-directed and LEDGF-directed integration sites. The ability to redirect HIV-1 DNA integration may help solve the problems associated with the activation of oncogenes when retroviruses are used in gene therapy.

Authors: Ferris, A; Wu, X; Hughes, C; Stewart, C; Smith, S

• Publication status: Published
• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Volume: 107
• Issue: 7
• Pages: 3135-3140
• Publication date: 2010-02-01
• DOI: 10.1073/pnas.0914142107
• EISSN: 1091-6490
• ISSN: 0027-8424
• Language: English
• Keywords: Cell Line; Animals; Binding Sites; Chromatin; Sequence Analysis, DNA; Flow Cytometry; Mice; Computational Biology; Protein Structure, Tertiary; Gene Expression Profiling; Homeodomain Proteins; DNA, Viral; HIV Integrase; HIV-1; Tumor Suppressor Proteins; Virus Integration; Mice, Knockout; Genetic Therapy; Intercellular Signaling Peptides and Proteins