IMR Press / FBL / Volume 9 / Issue 5 / DOI: 10.2741/1459

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on as a courtesy and upon agreement with Frontiers in Bioscience.

Open Access Article
Paradoxical effects of DNA binding polyamides on HTLV-1 transcription
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1 Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523-1870
2 Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO 80523-1870
3 Division of Chemistry and Chemical Engineering, 164-30, California Institute of Technology, Pasadena, CA 91125
Academic Editor:Susan Marriott
Front. Biosci. (Landmark Ed) 2004, 9(5), 3058–3067;
Published: 1 September 2004
(This article belongs to the Special Issue Taking control of the host: molecular strategies of HTLV-I infection)

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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