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

  1. Author:
    Ferris, A. L.
    Wu, X. L.
    Hughes, C. M.
    Stewart, C.
    Smith, S. J.
    Milne, T. A.
    Wang, G. G.
    Shun, M. C.
    Allis, C. D.
    Engelman, A.
    Hughes, S. H.

  2. Author Address

    [Ferris, Andrea L.; Smith, Steven J.; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Wu, Xiaolin; Stewart, Claudia] SAIC Frederick Inc, Lab Mol Technol, Frederick, MD 21702 USA. [Hughes, Christina M.; Milne, Thomas A.; Wang, Gang G.; Allis, C. David] Rockefeller Univ, Lab Chromatin Biol & Epigenet, New York, NY 10065 USA. [Shun, Ming-Chieh; Engelman, Alan] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA.;Hughes, SH, NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA.;hughesst@mail.nih.gov
    1. Year: 2010
    2. Date: Feb 16
    3. Epub Date: 2/6/2010
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 107
    2. 7
    3. Pages: 3135-3140
  4. Type of Article: Article
  5. ISSN: 0027-8424
  1. Abstract:

    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 1 alpha (HP1 alpha). The ING2 PHD finger binds H3K4me3, a histone mark that is associated with the transcriptional start sites of expressed genes. The HP1 alpha 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 HP1 alpha 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.

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External Sources

  1. View Full Text
  2. DOI: 10.1073/pnas.0914142107
  3. PMID: 20133638
  4. PMCID: PMC2840313
  5. View record in Web of Science®
  6. WOS: 000274599500077

Library Notes

  1. Fiscal Year: FY2009-2010
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