Bending studies of DNA site-specifically modified by cisplatin, trans-diamminedichloroplatinum(II) and cis-[Pt(NH3)2(N3-cytosine)Cl]+.
Duplex oligonucleotides containing a single intrastrand [Pt(NH3)2]2+ cross-link or monofunctional adduct and either 15 or 22 bp in length were synthesized and chemically characterized. The platinum-modified and unmodified control DNAs were polymerized in the presence of DNA ligase and the products studied on 8% native polyacrylamide gels. The extent of DNA bending caused by the various platinum-DNA adducts was revealed by their gel mobility shifts relative to unplatinated controls. The bifunctional adducts cis-[Pt(NH3)2[d(GpG)]]+, cis-[Pt(NH3)2[d(ApG)]]+, and cis-[Pt(NH3)2[d(G*pTpG*)]], where the asterisks denote the sites of platinum binding, all bend the double helix, whereas the adduct trans-[Pt(NH3)2[d(G*pTpG*)]] imparts a degree of flexibility to the duplex. When modified by the monofunctional adduct cis-[Pt(NH3)2(N3-cytosine)(dG)]Cl the helix remains rod-like. These results reveal important structural differences in DNAs modified by the antitumor drug cisplatin and its analogs that could be important in the biological processing of the various adducts in vivo.
Bellon
S F
SF
Department of Chemistry, Massachusetts Institute of Technology, Cambridge 02139.
Lippard
S J
SJ
D001345:Autoradiography; D001483:Base Sequence; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002945:Cisplatin / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects*; D006868:Hydrolysis; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D013054:Spectrophotometry, Atomic; D013237:Stereoisomerism
D009944:Organoplatinum Compounds; D004247:DNA; D002945:Cisplatin