Abstract
Ditercalinium is a synthetic anticancer drug that binds to DNA by bis-intercalation and activates DNA repair processes. In prokaryotes, noncovalent DNA-ditercalinium complexes are incorrectly recognized by the uvrABC repair system as covalent lesions on DNA. In eukaryotes, mitochondrial DNA is degraded by excess and futile DNA repair. Using x-ray crystallography, we have determined, to 1.7 A resolution, the three-dimensional structure of a complex of ditercalinium bound to the double-stranded DNA fragment [d(CGCG)]2. The DNA in the complex with ditercalinium is kinked (by 15 degrees) and severely unwound (by 36 degrees) with exceptionally wide major and minor grooves. Recognition of the DNA-ditercalinium complex by uvrABC in prokaryotes, and by mitochondrial DNA repair systems in eukaryotes, might be related to drug-induced distortion of the DNA helix.
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- Coll M., Frederick C. A., Wang A. H., Rich A. A bifurcated hydrogen-bonded conformation in the d(A.T) base pairs of the DNA dodecamer d(CGCAAATTTGCG) and its complex with distamycin. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8385–8389. doi: 10.1073/pnas.84.23.8385. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Delbarre A., Delepierre M., Garbay C., Igolen J., Le Pecq J. B., Roques B. P. Geometry of the antitumor drug ditercalinium bisintercalated into d(CpGpCpG)2 by 1H NMR. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2155–2159. doi: 10.1073/pnas.84.8.2155. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Delbarre A., Delepierre M., Igolen J., Le Pecq J. B., Roques B. P. 1H NMR study of the structure of a pyridocarbazole dimer-d[CpGpCpG] complex. Biochimie. 1985 Jul-Aug;67(7-8):823–828. doi: 10.1016/s0300-9084(85)80174-7. [DOI] [PubMed] [Google Scholar]
- Delbarre A., Delepierre M., Langlois d'Estaintot B., Igolen J., Roques B. P. Bisintercalation of ditercalinium into a d[CpGpCpG]2 minihelix: structure and dynamics aspects--a 400-MHz 1H-NMR study. Biopolymers. 1987 Jul;26(7):1001–1033. doi: 10.1002/bip.360260703. [DOI] [PubMed] [Google Scholar]
- Delepierre M., Igolen J., Roques B. P. Study of the bisintercalation of the antitumor drug ditercalinium by 31P-NMR. Biopolymers. 1988 Jun;27(6):957–968. doi: 10.1002/bip.360270606. [DOI] [PubMed] [Google Scholar]
- Delepierre M., Maroun R., Garbay-Jaureguiberry C., Igolen J., Roques B. P. 1H and 31P nuclear magnetic resonance studies of the differences in DNA deformation induced by anti-tumoral 7H-pyrido[4,3-c]carbazole dimers. J Mol Biol. 1989 Nov 5;210(1):211–228. doi: 10.1016/0022-2836(89)90301-x. [DOI] [PubMed] [Google Scholar]
- Frederick C. A., Williams L. D., Ughetto G., van der Marel G. A., van Boom J. H., Rich A., Wang A. H. Structural comparison of anticancer drug-DNA complexes: adriamycin and daunomycin. Biochemistry. 1990 Mar 13;29(10):2538–2549. [PubMed] [Google Scholar]
- Garbay-Jaureguiberry C., Laugâa P., Delepierre M., Laalami S., Muzard G., Le Pecq J. B., Roques B. P. DNA bis-intercalators as new anti-tumour agents: modulation of the anti-tumour activity by the linking chain rigidity in the ditercalinium series. Anticancer Drug Des. 1987 Apr;1(4):323–335. [PubMed] [Google Scholar]
- Jain S., Zon G., Sundaralingam M. Base only binding of spermine in the deep groove of the A-DNA octamer d(GTGTACAC). Biochemistry. 1989 Mar 21;28(6):2360–2364. doi: 10.1021/bi00432a002. [DOI] [PubMed] [Google Scholar]
- Lambert B., Jones B. K., Roques B. P., Le Pecq J. B., Yeung A. T. The noncovalent complex between DNA and the bifunctional intercalator ditercalinium is a substrate for the UvrABC endonuclease of Escherichia coli. Proc Natl Acad Sci U S A. 1989 Sep;86(17):6557–6561. doi: 10.1073/pnas.86.17.6557. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lambert B., Roques B. P., Le Pecq J. B. Induction of an abortive and futile DNA repair process in E. coli by the antitumor DNA bifunctional intercalator, ditercalinium: role in polA in death induction. Nucleic Acids Res. 1988 Feb 11;16(3):1063–1078. doi: 10.1093/nar/16.3.1063. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lambert B., Segal-Bendirdjian E., Esnault C., Le Pecq J. B., Roques B. P., Jones B., Yeung A. T. Recognition by the DNA repair system of DNA structural alterations induced by reversible drug-DNA interactions. Anticancer Drug Des. 1990 Feb;5(1):43–53. [PubMed] [Google Scholar]
- Lavery R., Pullman B. The dependence of the surface electrostatic potential of B-DNA on environmental factors. J Biomol Struct Dyn. 1985 Feb;2(5):1021–1032. doi: 10.1080/07391102.1985.10507618. [DOI] [PubMed] [Google Scholar]
- Léon P., Garbay-Jaureguiberry C., Barsi M. C., Le Pecq J. B., Roques B. P. Modulation of the antitumor activity by methyl substitutions in the series of 7H-pyridocarbazole monomers and dimers. J Med Chem. 1987 Nov;30(11):2074–2080. doi: 10.1021/jm00394a024. [DOI] [PubMed] [Google Scholar]
- Léon P., Garbay-Jaureguiberry C., Le Pecq J. B., Roques B. P. Relationship between the size and position of substituents on 7H-pyrido[4,3-c]carbazole monomers and dimers and their DNA binding and anti-tumor properties. Anticancer Drug Des. 1988 Jun;3(1):1–13. [PubMed] [Google Scholar]
- Maroun R., Delepierre M., Roques B. P. Intercalative binding of ditercalinium to d(CpGpCpG)2: a theoretical study. J Biomol Struct Dyn. 1989 Dec;7(3):607–621. doi: 10.1080/07391102.1989.10508510. [DOI] [PubMed] [Google Scholar]
- Pelaprat D., Delbarre A., Le Guen I., Roques B. P., Le Pecq J. B. DNA intercalating compounds as potential antitumor agents. 2. Preparation and properties of 7H-pyridocarbazole dimers. J Med Chem. 1980 Dec;23(12):1336–1343. doi: 10.1021/jm00186a010. [DOI] [PubMed] [Google Scholar]
- Quigley G. J., Teeter M. M., Rich A. Structural analysis of spermine and magnesium ion binding to yeast phenylalanine transfer RNA. Proc Natl Acad Sci U S A. 1978 Jan;75(1):64–68. doi: 10.1073/pnas.75.1.64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sancar A., Sancar G. B. DNA repair enzymes. Annu Rev Biochem. 1988;57:29–67. doi: 10.1146/annurev.bi.57.070188.000333. [DOI] [PubMed] [Google Scholar]
- Williams L. D., Egli M., Qi G., Bash P., van der Marel G. A., van Boom J. H., Rich A., Frederick C. A. Structure of nogalamycin bound to a DNA hexamer. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2225–2229. doi: 10.1073/pnas.87.6.2225. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Williams L. D., Egli M., Ughetto G., van der Marel G. A., van Boom J. H., Quigley G. J., Wang A. H., Rich A., Frederick C. A. Structure of 11-deoxydaunomycin bound to DNA containing a phosphorothioate. J Mol Biol. 1990 Sep 20;215(2):313–320. doi: 10.1016/S0022-2836(05)80349-3. [DOI] [PubMed] [Google Scholar]
- Williams L. D., Frederick C. A., Ughetto G., Rich A. Ternary interactions of spermine with DNA: 4'-epiadriamycin and other DNA: anthracycline complexes. Nucleic Acids Res. 1990 Sep 25;18(18):5533–5541. doi: 10.1093/nar/18.18.5533. [DOI] [PMC free article] [PubMed] [Google Scholar]