DNA sequence specificity of mitoxantrone.
An in vitro transcription assay was used to determine the sequence specificity of binding of mitoxantrone to a 497 bp fragment of DNA containing the lac UV5 promoter. Transcriptional blockages of the E. coli RNA polymerase were observed dominantly prior to 5'-CpA sequences (64% occurrence), and to a lesser extent 5'-CpG sequences (29%). Overall, 93% of all blockage sites were prior to pyrimidine (3'-5') purine sequences. An effect of flanking sequences was evident since the blockage sites contained an A/T base pair 5' prior to the consensus CpA and CpG intercalation sites. The consensus sequences for the preferred mitoxantrone intercalation sites are therefore 5'-(A/T)CA and 5'-(A/T)CG. The location of transcriptional blockages one base pair prior to the intercalation site is consistent with the fact that the mitoxantrone side chains lie in the major groove.
Panousis
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Department of Biochemistry, La Trobe University, Bundoora, Victoria, Australia.
Phillips
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D001483:Base Sequence; D001665:Binding Sites; D016384:Consensus Sequence; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D008942:Mitoxantrone / Q000378:metabolism* / Q000494:pharmacology; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic / Q000187:drug effects*
D004247:DNA; D008942:Mitoxantrone