Lens epithelium-derived growth factor fusion proteins redirect HIV-1 DNA integration.
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.
HIV Drug Resistance Program, National Cancer Institute, Frederick, MD 21702, USA.
Andrea L
AL
Ferris
Xiaolin
X
Wu
Christina M
CM
Hughes
Claudia
C
Stewart
Steven J
SJ
Smith
Thomas A
TA
Milne
Gang G
GG
Wang
Ming-Chieh
MC
Shun
C David
CD
Allis
Alan
A
Engelman
Stephen H
SH
Hughes
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D019295:Computational Biology; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015316:Genetic Therapy / Q000379:methods; D019427:HIV Integrase / Q000378:metabolism; D015497:HIV-1; D018398:Homeodomain Proteins / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D017422:Sequence Analysis, DNA; D025521:Tumor Suppressor Proteins / Q000235:genetics; D016662:Virus Integration / Q000502:physiology*
D002843:Chromatin; D004279:DNA, Viral; D018398:Homeodomain Proteins; C512177:ING2 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D025521:Tumor Suppressor Proteins; C119380:lens epithelium-derived growth factor; D019427:HIV Integrase