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Inhibition of RNA polymerase II transcription in human cells by synthetic DNA-binding ligands

Dickinson, Liliane A. and Gulizia, Richard J. and Trauger, John W. and Baird, Eldon E. and Mosier, Donald E. and Gottesfeld, Joel M. and Dervan, Peter B. (1998) Inhibition of RNA polymerase II transcription in human cells by synthetic DNA-binding ligands. Proceedings of the National Academy of Sciences of the United States of America, 95 (22). pp. 12890-12895. ISSN 0027-8424. http://resolver.caltech.edu/CaltechAUTHORS:DICpnas98

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Abstract

Sequence-specific DNA-binding small molecules that can permeate human cells potentially could regulate transcription of specific genes. Multiple cellular DNA-binding transcription factors are required by HIV type 1 for RNA synthesis. Two pyrrole-imidazole polyamides were designed to bind DNA sequences immediately adjacent to binding sites for the transcription factors Ets-l, lymphoid-enhancer binding factor 1, and TATA-box binding protein. These synthetic ligands specifically inhibit DNA-binding of each transcription factor and HIV type 1 transcription in cell-free assays. When used in combination, the polyamides inhibit virus replication by >99% in isolated human peripheral blood lymphocytes, with no detectable cell toxicity, The ability of small molecules to target predetermined DNA sequences located within RNA polymerase II promoters suggests a general approach for regulation of gene expression, as well as a mechanism for the inhibition of viral replication.


Item Type:Article
Additional Information:Copyright © 1998 by the National Academy of Sciences. Contributed by Peter B. Dervan, August 20, 1998. We are grateful to the National Institutes of Health for grants to P.B.D, J.M.G., and D.E.M. for research support, the National Science Foundation and the Ralph M. Parsons Foundation for predoctoral fellowships to J.W.T., and the Howard Hughes Medical Institute for a predoctoral fellowship to E.E.B. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Subject Keywords:HIV TYPE 1; VIRAL REPLICATION; HAIRPIN POLYAMIDE; DNA RECOGNITION; IMMUNODEFICIENCY-VIRUS TYPE-1; SEQUENCE-SPECIFIC RECOGNITION; PYRROLE-IMIDAZOLE POLYAMIDES; LONG TERMINAL REPEAT; PBL-SCID MICE; CD4+ T-CELLS; MINOR-GROOVE; ETS-DOMAIN; CRYSTAL-STRUCTURE; GENE-EXPRESSION
Record Number:CaltechAUTHORS:DICpnas98
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:DICpnas98
Alternative URL:http://www.pnas.org/cgi/content/abstract/95/22/12890
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:1555
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:30 Jan 2006
Last Modified:26 Dec 2012 08:44

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