Homodinuclear (Pt,Pt) and heterodinuclear (Ru,Pt) metal compounds as DNA-protein cross-linking agents: potential suicide DNA lesions.
Homodinuclear (Pt,Pt) and heterodinuclear (Ru,Pt) metal compounds having the generalized formula M(a)NH2(CH)4NH2M(b) are shown to form specific DNA lesions which can efficiently cross-link proteins to DNA. In this study, the homodinuclear case is represented by M(a) = M(b) = [cis-Pt(Cl2)-(NH3)] and the heterodinuclear case is represented by M(a) = [cis-RuCl2(DMSO)3] and M(b) = [cis-PtCl2(NH3)]. Native and denaturing polyacrylamide gel electrophoresis was used to show the formation of ternary coordination complexes between the metal-treated 49-bp DNA fragment and the Escherichia coli UvrA and UvrB DNA repair proteins. Treatment with proteinase K results in loss of the DNA-protein cross-links. DNA-protein cross-links formed between UvrA and DNA previously modified with the dinuclear metal compounds are reversible with the reducing agent beta-mercaptoethanol. The DNA lesion responsible for efficient DNA-protein cross-linking is most probably a DNA-DNA interstrand cross-link in which each metal atom is coordinated with one strand of the DNA helix. The formation of DNA repair protein associated DNA cross-links, potential "suicide adducts", suggests a novel action mechanism for these anticancer compounds. In addition, these dinuclear metal compounds should be very useful agents for the investigation of a wide range of protein-DNA interactions.
Van Houten
B
B
Department of Pathology, Vermont Cancer Center, Burlington 05405.
Illenye
S
S
Qu
Y
Y
Farrell
N
N
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000970:Antineoplastic Agents; D001426:Bacterial Proteins / Q000378:metabolism*; D001483:Base Sequence; D002945:Cisplatin; D003432:Cross-Linking Reagents; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004249:DNA Damage; D004265:DNA Helicases; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019286:Endopeptidase K; D004926:Escherichia coli / Q000378:metabolism; D029968:Escherichia coli Proteins; D007700:Kinetics; D008961:Models, Structural; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D009944:Organoplatinum Compounds; D012697:Serine Endopeptidases
D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D009838:Oligodeoxyribonucleotides; D009944:Organoplatinum Compounds; C058093:UvrB protein, E coli; C034697:transplatin; C084229:N-(dichlorotris(dimethylsulfoxide)ruthenium(II))-N-(amminedichloroplatinum(II))butane-1,4-diamine; D004247:DNA; D012697:Serine Endopeptidases; D019286:Endopeptidase K; C068631:UvrA protein, E coli; D000251:Adenosine Triphosphatases; D004265:DNA Helicases; D002945:Cisplatin