DOI: 10.1073/pnas.0914142107. Lens epithelium-derived growth factor fusion proteins redirect HIV-1 DNA integration

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

10.1073/pnas.0914142107

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

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 1α (HP1α). The ING2 PHD finger binds H3K4me3, a histone mark that is associated with the transcriptional start sites of expressed genes. The HP1α 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 HP1α 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.

Bibliography

Ferris, A. L., Wu, X., 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. (2010). Lens epithelium-derived growth factor fusion proteins redirect HIV-1 DNA integration. Proceedings of the National Academy of Sciences, 107(7), 3135â3140.

Authors 11

Andrea L. Ferris (first)
Xiaolin Wu (additional)
Christina M. Hughes (additional)
Claudia Stewart (additional)
Steven J. Smith (additional)
Thomas A. Milne (additional)
Gang G. Wang (additional)
Ming-Chieh Shun (additional)
C. David Allis (additional)
Alan Engelman (additional)
Stephen H. Hughes (additional)

References 34 Referenced 117

Dates

Type	When
Created	15 years, 7 months ago (Feb. 1, 2010, 10:51 p.m.)
Deposited	3 years, 4 months ago (April 12, 2022, 7:20 p.m.)
Indexed	6 days, 14 hours ago (Aug. 30, 2025, 12:56 p.m.)
Issued	15 years, 7 months ago (Feb. 1, 2010)
Published	15 years, 7 months ago (Feb. 1, 2010)
Published Online	15 years, 7 months ago (Feb. 1, 2010)
Published Print	15 years, 6 months ago (Feb. 16, 2010)

Funders 0

None

BibTeX

@article{Ferris_2010, title={Lens epithelium-derived growth factor fusion proteins redirect HIV-1 DNA integration}, volume={107}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.0914142107}, DOI={10.1073/pnas.0914142107}, number={7}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Ferris, Andrea L. and Wu, Xiaolin and Hughes, Christina M. and Stewart, Claudia and Smith, Steven J. and Milne, Thomas A. and Wang, Gang G. and Shun, Ming-Chieh and Allis, C. David and Engelman, Alan and Hughes, Stephen H.}, year={2010}, month=feb, pages={3135–3140} }

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  "abstract": "<jats:p>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\u03b1 (HP1\u03b1). The ING2 PHD finger binds H3K4me3, a histone mark that is associated with the transcriptional start sites of expressed genes. The HP1\u03b1 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\u03b1 chromodomain was linked to the LEDGF IBD directed integrations to sites that differed from both the PHD finger fusion\u2013directed 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.</jats:p>",
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