DNA structural reorganization upon conversion of a psoralen furan-side monoadduct to an interstrand cross-link: implications for DNA repair.
We have used 1H NMR spectroscopy to determine the structural changes induced in the DNA oligomer d(5'-GCGTACGC-3')2 upon conversion of the 4'-hydroxy-methyl-4,5',8-trimethylpsoralen-DNA furan-side monoadduct (MAf) to the interstrand cross-link (XL). The MAf is a photochemical intermediate on the path to interstrand XL and has the psoralen intercalated into the helix. The local DNA structure is distorted in both adducts, but it returns to normal within three base pairs. The formation of XL requires displacement of the psoralen toward the initially unmodified strand, accompanied by a change in the hybridization of the thymine C-5 and C-6 carbons and a change in the local helix twist. The MAf is intercalated in the helix. There is no significant bend in the helix axis of either the MAf or XL. There are significant changes in the local helix dynamics upon photoadduct formation that may be recognized by cellular DNA repair enzyme systems. We hypothesize that the repair enzymes target lesions by detecting the conformational flexibility of the sugar-phosphate backbone induced by DNA-damaging agents.
Spielmann
H P
HP
Structural Biology Division, Lawrence Berkeley Laboratory, Berkeley, CA 94720.
Dwyer
T J
TJ
Sastry
S S
SS
Hearst
J E
JE
Wemmer
D E
DE
D001483:Base Sequence; D004247:DNA / Q000737:chemistry* / Q000187:drug effects; D004260:DNA Repair; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry*; D009626:Terminology as Topic; D014307:Trioxsalen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D009838:Oligodeoxyribonucleotides; C016507:hydroxymethyltrioxsalen; D004247:DNA; D014307:Trioxsalen