Sequence preference for strand cleavage of gapped duplexes by dynemicin A: possible mechanism of sequence-dependent double-stranded breaks.
A double-stranded DNA cleavage mechanism by a novel enediyne type antitumor antibiotic, dynemicin A, has been investigated through sequence-dependent strand breakage of a series of duplexes containing a single nucleotide gap. We found that (1) dynemicin A breaks specifically at the 3'-shifted position by one base opposite the gap, (2) the strong cleavage is detected at 5'-Pu_Pu/3'-PyPuPy sequences, and (3) dynemicin H (aromatized form of dynemicin A) gives only a small inhibition effect (20%) on the cleavage of gapped duplex by dynemicin A. The long half-life of aromatization of dynemicin A (118 min, in the presence of DNA) obtained from HPLC analysis provides enough time for the second cleavage. The present results strongly indicate a two-step mechanism for the double-stranded DNA scission of dynemicin A. Namely, this double-stranded break is caused by two drug molecules, each of which cuts one DNA strand.
Kusakabe
T
T
Institute for Chemical Research, Kyoto University, Japan.
Uesugi
M
M
Sugiura
Y
Y
D000475:Alkenes; D000880:Anthraquinones / Q000378:metabolism / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D004278:DNA, Superhelical / Q000187:drug effects; D053281:Enediynes; D007364:Intercalating Agents / Q000494:pharmacology; D008956:Models, Chemical; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D013864:Thioglycolates
D000475:Alkenes; D000880:Anthraquinones; D000903:Antibiotics, Antineoplastic; D004278:DNA, Superhelical; D053281:Enediynes; D007364:Intercalating Agents; D009838:Oligodeoxyribonucleotides; D013864:Thioglycolates; C068022:dynemicin H; D004247:DNA; C061229:dynemicin A; C037474:methyl thioglycolate