Promoter-specific inhibition of transcription by daunorubicin in Saccharomyces cerevisiae.
Several anti-tumour drugs exert some of their cytotoxic effects by direct binding to DNA, thus inhibiting the transcription of certain genes. We analysed the influence of the anti-tumour antibiotic daunorubicin on the transcription of different genes in vivo using the budding yeast Saccharomyces cerevisiae. Daunorubicin only affected wild-type yeast strains at very high concentrations; however, erg6 mutant strains (but not pdr1, pdr3 or pdr5 strains) were sensitive to daunorubicin at low micromolar concentrations. In Delta erg6 strains, daunorubicin inhibited the galactose-induced transcription by Gal4p in a specific manner, since the transcription of identical reporters driven by other activators (either constitutive or inducible) was not inhibited. The drug concentrations at which Gal4p function was inhibited did not affect cell growth or viability. Furthermore, daunorubicin inhibited the growth in galactose and the transcriptional induction of resident Gal4p-driven genes upon galactose addition, two processes absolutely dependent on Gal4p function. We propose that daunorubicin and some transcription factors compete for DNA sequences encompassing CpG steps, and that this is the main determinant of the effects of the drug on transcription in vivo. Our approach may foster the development of anti-tumour drugs with more specific mechanisms of action.
Marín
Silvia
S
Instituto de Biología Molecular de Barcelona, CSIC, Jordi Girona, 18-26, 08034 Barcelona, Spain.
Mansilla
Sylvia
S
García-Reyero
Natàlia
N
Rojas
Marta
M
Portugal
José
J
Piña
Benjamin
B
D000970:Antineoplastic Agents / Q000494:pharmacology*; D004268:DNA-Binding Proteins; D003630:Daunorubicin / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C052130:GAL4 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D003630:Daunorubicin