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.
Ferris
Andrea L
AL
HIV Drug Resistance Program, National Cancer Institute, Frederick, MD 21702, USA.
Wu
Xiaolin
X
Hughes
Christina M
CM
Stewart
Claudia
C
Smith
Steven J
SJ
Milne
Thomas A
TA
Wang
Gang G
GG
Shun
Ming-Chieh
MC
Allis
C David
CD
Engelman
Alan
A
Hughes
Stephen H
SH
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