Drug Inhibitors of RNA Polymerase II Transcription

Abstract

Transcription by RNA polymerase II occurs after formation of a transcription complex. This complex is assembled in stages by the interaction of transcription factors with the template and/or with each other. We report on the ability of six drugs to inhibit the assembly of the RNA polymerase II transcription complex. Assembly of the complex on the adenovirus major late promoter requires several transcription factors. The normal assembly process requires that the DNA first interact with TFIIA, then with TFIID, and finally with at least four additional transcription factors (one of which is RNA polymerase II). We observe that streptolydigin (10 μ/ml) inhibits association of IIA and IID, and at higher concentrations (100 μg/ml) inhibits that IIA/IID complex from binding to DNA. Streptovaricin (100 μg/ml) appears to inhibit the IIA/ IID interaction with DNA and prevents reinitiation (at 500 μg/ml). Adriamycin (1 μg/ml) inhibits the interaction of TFIID with the IIA/DNA complex and inhibits an additional event immediately prior to, or during, elongation. Daunorubicin may be an elongation inhibitor. Heparin at 10 μg/ml inhibits further assembly after the IIA/IID/DNA complex has formed, and at 100 μg/ml also inhibits a late event in the assembly process and blocks reinitiation. Rifamycin AF/013 (100 μg/ml) inhibits the early events necessary to form the IIA/IID/DNA complex and (at 10 μg/ml) an assembly event following formation of the IIA/IID/DNA complex. Therefore, these compounds should be useful as probes for further examination of the assembly process.