Drug-induced DNA repair: X-ray structure of a DNA-ditercalinium complex.
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.
Gao
Q
Q
Department of Biology, Massachusetts Institute of Technology, Cambridge 02139.
Williams
L D
LD
Egli
M
M
Rabinovich
D
D
Chen
S L
SL
Quigley
G J
GJ
Rich
A
A
D001483:Base Sequence; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry* / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D007364:Intercalating Agents / Q000494:pharmacology; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry*; D014961:X-Ray Diffraction / Q000379:methods
D002227:Carbazoles; D007364:Intercalating Agents; D009838:Oligodeoxyribonucleotides; D004247:DNA; C042804:ditercalinium