Conformation-selective DNA strand breaks by dynemicin: a molecular wedge into flexible regions of DNA.
We present evidence that the enediyne antitumor antibiotic dynemicin recognizes and cleaves conformationally flexible regions of DNA. This is based on specific strand breaks at mismatches, bulges, and nicks as determined by high-resolution sequencing gels. On the basis of the weak association constant of dynemicin for DNA, it is expected that these more flexible regions would be preferred sites. In addition, the DNA unwinding behavior of dynemicin and the absorption spectrum of the dynemicin-DNA complex are strongly indicative of its intercalative binding with DNA. The results allow us to propose dynemicin as a molecular wedge that binds to the DNA by intercalating into the minor-groove side of conformationally flexible regions of DNA. Presumably, DNA local flexibility is able to create an open pocket in the minor groove, permits facile intercalation of dynemicin, and then increases the chances of its DNA damaging event. Implications for the biological action of dynemicin have also been discussed.
Kusakabe
T
T
Institute for Chemical Research, Kyoto University, Japan.
Maekawa
K
K
Ichikawa
A
A
Uesugi
M
M
Sugiura
Y
Y
D000880:Anthraquinones / Q000378:metabolism / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D004249:DNA Damage; D053281:Enediynes; D007364:Intercalating Agents / Q000378:metabolism / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000378:metabolism
D000880:Anthraquinones; D000903:Antibiotics, Antineoplastic; D053281:Enediynes; D007364:Intercalating Agents; D009838:Oligodeoxyribonucleotides; C061229:dynemicin A