Abstract
Under superhelical stress, oligopurine-oligopyrimidine mirror-repeat sequences are able to adoptH-DNA conformations where a triple-helical and a single-stranded structure co-exist. We have previously shown that a benzo[e]pyridonindole derivative (BePI), an antitumor drug interacting more tightly with triplex than with duplex DNA, strongly stabilizes intermolecular triple helices formed upon binding of homopyrimidine oligonucleotides to the major groove of double-stranded DNA at oligopurine-oligopyrimidine sequences. Here we show that an intramolecular triple helix is also strongly stabilized by this ligand.In vitroelongation performed by different DNA polymerases (bacteriophage T7,Escherichia coliorTaqpolymerase) could be irreversibly inhibited by theH-DNA structure in the presence of BePI. A mirror-repeat polypurine-polypyrimidine sequence inserted between theE. coliβ-lactamase gene (conferring ampicillin resistance) and itsblapromoter strongly inhibited transcription of the β-lactamase genein vivo. In the absence of supercoiling, transition to theH-conformation did not occur, but BePI stabilized theH-DNA structure induced by supercoiling as shown by chemical probes (chloroacetaldehyde). The results presented here open a new field of investigation for antitumor agents targeted to a novel class of genetic structures able to regulate gene expression.
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