Nucleic Acids Research, Vol 27, Issue 17 3402-3409, Copyright © 1999 by Oxford University Press
B Martin, A Vaquero, W Priebe and J Portugal
An in vitro transcription assay was used to compare the capacity of the
bisintercalating anthracycline WP631 (which displays a remarkably high
DNA-binding affinity) and the monointercalating anthracycline daunomycin to
inhibit transcription initiation of the adenovirus major late promoter
linked to a G-less transcribed DNA template. Both drugs inhibit basal RNA
synthesis in a concentration-dependent way, and the drug concentrations
required to inhibit transcription initiation are similar. However, in this
study WP631 was around 15 times more efficient at inhibiting transcription
initiation when used with an adenovirus promoter containing an upstream
Sp1-protein binding site under experimental conditions in which the Sp1
protein acted as a transactivator in vitro. The differences in the ability
of each drug to inhibit transcription initiation were related to the
competition between Sp1 and the drugs for the same binding site.
Concentrations of WP631 as low as 60 nM could inhibit the Sp1-activated
transcription initiation in vitro. In contrast, the concentration of
daunomycin required to inhibit Sp1-activated transcription by 50% was
almost the same as the concentration required to inhibit basal
transcription. The efficiency of WP631 at displacing Sp1 from its putative
binding site was confirmed using gel retardation and footprinting assays.
These results are the first unequivocal example of a direct effect of an
intercalator on activated transcription initiation.
ARTICLES
Bisanthracycline WP631 inhibits basal and Sp1-activated transcription initiation in vitro
Departamento de Biologia Molecular y Celular, Instituto de Biologia Molecular de Barcelona, CSIC, Jordi Girona 18-26, 08034 Barcelona, Spain.
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