Novel small-molecule inhibitors of RNA polymerase III

Liping Wu, Jing Pan, Vala Thoroddsen, Deborah R. Wysong, Ronald K. Blackman, Christine E. Bulawa, Alexandra E. Gould, Timothy D. Ocain, Lawrence R. Dick, Patrick Errada, Patrick K. Dorr, Tanya Parkinson, Tony Wood, Daniel Kornitzer, Ziva Weissman, Ian M. Willis, Karen McGovern

Research output: Contribution to journalArticle

50 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)256-264
Number of pages9
JournalEukaryotic Cell
Volume2
Issue number2
DOIs
StatePublished - Apr 2003

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RNA Polymerase III
DNA-directed RNA polymerase
transcription (genetics)
Transfer RNA
Saccharomyces cerevisiae
Yeasts
yeasts
mutants
assays
Candida albicans
cell growth
cells
mutation
Mutation
synthesis
Enzymes
Growth
enzymes
Genes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Microbiology

Cite this

Wu, L., Pan, J., Thoroddsen, V., Wysong, D. R., Blackman, R. K., Bulawa, C. E., ... McGovern, K. (2003). Novel small-molecule inhibitors of RNA polymerase III. Eukaryotic Cell, 2(2), 256-264. https://doi.org/10.1128/EC.2.2.256-264.2003

Novel small-molecule inhibitors of RNA polymerase III. / Wu, Liping; Pan, Jing; Thoroddsen, Vala; Wysong, Deborah R.; Blackman, Ronald K.; Bulawa, Christine E.; Gould, Alexandra E.; Ocain, Timothy D.; Dick, Lawrence R.; Errada, Patrick; Dorr, Patrick K.; Parkinson, Tanya; Wood, Tony; Kornitzer, Daniel; Weissman, Ziva; Willis, Ian M.; McGovern, Karen.

In: Eukaryotic Cell, Vol. 2, No. 2, 04.2003, p. 256-264.

Research output: Contribution to journalArticle

Wu, L, Pan, J, Thoroddsen, V, Wysong, DR, Blackman, RK, Bulawa, CE, Gould, AE, Ocain, TD, Dick, LR, Errada, P, Dorr, PK, Parkinson, T, Wood, T, Kornitzer, D, Weissman, Z, Willis, IM & McGovern, K 2003, 'Novel small-molecule inhibitors of RNA polymerase III', Eukaryotic Cell, vol. 2, no. 2, pp. 256-264. https://doi.org/10.1128/EC.2.2.256-264.2003
Wu L, Pan J, Thoroddsen V, Wysong DR, Blackman RK, Bulawa CE et al. Novel small-molecule inhibitors of RNA polymerase III. Eukaryotic Cell. 2003 Apr;2(2):256-264. https://doi.org/10.1128/EC.2.2.256-264.2003
Wu, Liping ; Pan, Jing ; Thoroddsen, Vala ; Wysong, Deborah R. ; Blackman, Ronald K. ; Bulawa, Christine E. ; Gould, Alexandra E. ; Ocain, Timothy D. ; Dick, Lawrence R. ; Errada, Patrick ; Dorr, Patrick K. ; Parkinson, Tanya ; Wood, Tony ; Kornitzer, Daniel ; Weissman, Ziva ; Willis, Ian M. ; McGovern, Karen. / Novel small-molecule inhibitors of RNA polymerase III. In: Eukaryotic Cell. 2003 ; Vol. 2, No. 2. pp. 256-264.
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