Novel Small-Molecule Inhibitors of RNA Polymerase III
Open Access
- 1 April 2003
- journal article
- Published by American Society for Microbiology in Eukaryotic Cell
- Vol. 2 (2), 256-264
- https://doi.org/10.1128/ec.2.2.256-264.2003
Abstract
A genetic approach utilizing the yeast Saccharomyces cerevisiae was used to identify the target of antifungal compounds. This analysis led to the identification of small molecule inhibitors of RNA polymerase (Pol) III from Saccharomyces cerevisiae. Three lines of evidence show that UK-118005 inhibits cell growth by targeting RNA Pol III in yeast. First, a dominant mutation in the g domain of Rpo31p, the largest subunit of RNA Pol III, confers resistance to the compound. Second, UK-118005 rapidly inhibits tRNA synthesis in wild-type cells but not in UK-118005 resistant mutants. Third, in biochemical assays, UK-118005 inhibits tRNA gene transcription in vitro by the wild-type but not the mutant Pol III enzyme. By testing analogs of UK-118005 in a template-specific RNA Pol III transcription assay, an inhibitor with significantly higher potency, ML-60218, was identified. Further examination showed that both compounds are broad-spectrum inhibitors, displaying activity against RNA Pol III transcription systems derived from Candida albicans and human cells. The identification of these inhibitors demonstrates that RNA Pol III can be targeted by small synthetic molecules.Keywords
This publication has 38 references indexed in Scilit:
- Transcriptional Profiling Shows that Gcn4p Is a Master Regulator of Gene Expression during Amino Acid Starvation in YeastMolecular and Cellular Biology, 2001
- The WD protein Cpc2p is required for repression of Gcn4 protein activity in yeast in the absence of amino‐acid starvationMolecular Microbiology, 1999
- Drug target validation and identification of secondary drug target effects using DNA microarraysNature Medicine, 1998
- Mechanistic aspects of tagetitoxin inhibition of RNA polymerase from Escherichia coliBiochemistry, 1994
- Construction of Small‐Insert Libraries Enriched for Short Tandem Repeat Sequences by Marker SelectionCurrent Protocols in Human Genetics, 1994
- Cerulenin-resistant mutants of Saccharomyces cerevisiae with an altered fatty acid synthase geneMolecular Genetics and Genomics, 1994
- Cyclosporin A, FK506 and rapamycin: more than just immunosuppressionTrends in Biochemical Sciences, 1993
- TRANSCRIPTION BY RNA POLYMERASE IIIAnnual Review of Biochemistry, 1988
- Extensive homology among the largest subunits of eukaryotic and prokaryotic RNA polymerasesCell, 1985
- Eukaryotic RNA PolymeraseCritical Reviews in Biochemistry, 1985