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Anti-repression of RNA polymerase II transcription by pyrrole-imidazole polyamides

Dickinson, Liliane A. and Trauger, John W. and Baird, Eldon E. and Ghazal, Peter and Dervan, Peter B. and Gottesfeld, Joel M. (1999) Anti-repression of RNA polymerase II transcription by pyrrole-imidazole polyamides. Biochemistry, 38 (33). pp. 10801-10807. ISSN 0006-2960. doi:10.1021/bi9912847.

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Pyrrole-imidazole polyamides are ligands that bind in the minor groove of DNA with high affinity and sequence selectivity. Molecules of this class have been shown to disrupt specific transcription factor-DNA interactions and to inhibit basal and activated transcription from various RNA polymerase II and III promoters. A set of eight-ring hairpin-motif pyrrole-imidazole polyamides has been designed to bind within the binding site for the human cytomegalovirus (CMV) UL122 immediate early protein 2 (IE86). IE86 represses transcription of the CMV major immediate early promoter (MIEP) through its cognate cis recognition sequence (crs) located between the TATA box and the transcription initiation site. The designed polyamides bind to their target DNA sequence with nanomolar affinities and with a high degree of sequence selectivity. The polyamides effectively block binding of IE86 protein to the crs in DNase I footprinting experiments. A mismatch polyamide, containing a single imidazole to pyrrole substitution, and also a polyamide binding to a site located 14 base pairs upstream of the repressor binding site, do not prevent IE86 binding to the crs. IE86-mediated transcriptional repression in vitro is relieved by a match polyamide but not by a mismatch polyamide. Transcription from a DNA template harboring a mutation in the crs is not affected either by IE86 protein or by the match polyamides. These results demonstrate that this new class of small molecules, the pyrrole-imidazole polyamides, are not only effective inhibitors of basal and activated transcription, but also can be used to activate transcription by blocking the DNA-binding activity of a repressor protein.

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Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 1999 American Chemical Society. Received June 4, 1999; Publication Date (Web): July 27, 1999. This work was supported by National Institutes of Health Grants GM57148 (to J.M.G. and P.B.D.), CA66167 (to P.G.), and GM51747 (to P.B.D.). The National Science Foundation and the Ralph M. Parsons Foundation provided predoctoral support for J.W.T., and the Howard Hughes Medical Institute provided a predoctoral fellowship for E.E.B. P.G. is a Scholar of the Leukemia Society of America. We thank Dr. Jennifer Nyborg (Colorado State University) for providing the CEM nuclear extract.
Funding AgencyGrant Number
NSF Predoctoral FellowshipUNSPECIFIED
Ralph M. Parsons FoundationUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Leukemia Society of AmericaUNSPECIFIED
Issue or Number:33
Record Number:CaltechAUTHORS:20160510-093227451
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Official Citation:Anti-repression of RNA Polymerase II Transcription by Pyrrole−Imidazole Polyamides Liliane A. Dickinson, John W. Trauger, Eldon E. Baird, Peter Ghazal, Peter B. Dervan, and Joel M. Gottesfeld Biochemistry 1999 38 (33), 10801-10807 DOI: 10.1021/bi9912847
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66859
Deposited By: Victoria Brennan
Deposited On:18 May 2016 21:29
Last Modified:11 Nov 2021 00:23

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