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Paradoxical effects of DNA binding polyamides on HTLV-1 transcription

Livengood, Jill A. and Fechter, Eric J. and Dervan, Peter B. and Nyborg, Jennifer K. (2004) Paradoxical effects of DNA binding polyamides on HTLV-1 transcription. Frontiers in Bioscience, 9 . pp. 3058-3067. ISSN 1093-9946. doi:10.2741/1459.

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Human T-cell leukemia virus type-1 (HTLV-1) depends on the virally encoded transcription factor Tax for efficient viral replication and gene expression. In a complex with CREB, Tax contacts the minor groove of the promoter DNA at guanine and cytosine rich sequences that flank three of the off-consensus cyclic-AMP response elements (CREs). In this study, we used six Tax-directed pyrrole-imidazole polyamides specifically designed to block Tax binding to DNA at each GC sequence of the three viral CREs. We found that four of these polyamides disrupt binding of the Tax/CREB complex in vitro, and that these same molecules also inhibit Tax-mediated transcription in vitro on chromatin-assembled templates. However, of these four Tax/CREB-specific polyamides, only one polyamide appears to be uniquely Tax specific. We show that polyamides can enter the nuclei of HTLV-1 infected T-cells, and two of the four polyamides down-regulated virion production in these cells. Together, these data illustrate the importance of studying polyamide inhibition of gene expression in vitro and in vivo, as the function of the polyamides in living cells is not fully understood. Finally, our data indicates that targeted disruption of the Tax/CREB complex, or other complexes which assemble on the HTLV-1 promoter, may provide a novel approach for inhibiting viral replication in vivo.

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Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 2005 Frontiers in Bioscience. We thank Dr. Barbara Bernstein for help with confocal imaging. We also thank Joel Gottesfeld for helpful discussions. We would also like to thank Matthew Lewis, Megan Morrell, Jeanne Mick, and Dinaida Lopez for their contribution to this work. This work was supported by NIH grants R01 CA55035 (to J.K.N.), and R01GM51747 (to P.B.D.).
Funding AgencyGrant Number
NIHR01 CA55035
Subject Keywords:Polyamide, Transcription, Tax, HTLV-1
Record Number:CaltechAUTHORS:20160509-114910480
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66768
Deposited By: Victoria Brennan
Deposited On:17 May 2016 22:33
Last Modified:11 Nov 2021 00:02

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