Sequence specificity of alkali-labile DNA damage photosensitized by suprofen.
On irradiation at UVB wavelengths, in aerated neutral aqueous solution, the anti-inflammatory drug suprofen (SP) photosensitizes the production of alkali-labile cleavage sites in DNA much more efficiently than direct strand breaks. It is active at submillimolar concentrations despite having no significant binding affinity for DNA. Gel sequencing studies utilizing 32P-end-labeled oligonucleotides have revealed that piperidine-sensitive lesions are formed predominantly at the positions of guanine (G) bases, with the extent of modification being UV dose- and SP concentration-dependent. Quite distinct patterns of G-specific damage are observed in single-stranded and duplex DNA molecules. The uniform attack at all G residues in single-stranded DNA, which is enhanced in D2O, is compatible with a Type-II mechanism. SP is a known generator of singlet oxygen whose participation in the reaction is supported by the effects of quenchers and scavengers. In duplex DNA, piperidine-induced cleavage occurs with high selectivity at the 5'-G of GG and (less prominently) GA doublets. This behavior is characteristic of a Type-I process involving electron transfer from DNA to photoexcited SP molecules. The ability of SP to sensitize the formation of Type-I and Type-II photo-oxidation products from 2'-deoxyguanosine attests to the feasibility of competing mechanisms in DNA.
Starrs
S M
SM
School of Biology and Biochemistry, Medical Biology Center, Queen's University, Belfast, Northern Ireland.
Davies
R J
RJ
D000468:Alkalies / Q000737:chemistry*; D001483:Base Sequence; D004247:DNA / Q000528:radiation effects; D004249:DNA Damage; D009841:Oligonucleotides; D017319:Photosensitizing Agents / Q000494:pharmacology*; D013496:Suprofen / Q000494:pharmacology*
D000468:Alkalies; D009841:Oligonucleotides; D017319:Photosensitizing Agents; D004247:DNA; D013496:Suprofen