title: Oxygen independent DNA interstrand cross-link formation by a nucleotide radical.
abstract: A 5-(2'-Deoxyuridinyl)methyl radical (1) was independently generated from three photochemical precursors and is the first example of a DNA radical that forms interstrand cross-links. Oxygen labeling experiments support generation of 1 by all precursors. Interstrand cross-links are produced upon irradiation of DNA containing any of the precursors. Cross-linking occurs via reaction with the opposing 2'-deoxyadenosine and is independent of O(2). The independence of cross-link formation on O(2) is explained by kinetic analysis, which shows that the radical reacts reversibly with O(2). Examination of the effects of glutathione on cross-link formation under anaerobic conditions suggests that adoption of the syn-conformation by 1 is the rate-limiting step in the process. Interstrand cross-link formation is reversible in the presence of a good nucleophile. The stability of the interstrand cross-link suggests that the isolated molecule is a rearrangement product of that formed in solution. The rearrangement is a consequence of the isolation procedure but also occurs slowly in solution. Oxygen independent cross-link formation may be useful for the purposeful damage of DNA in hypoxic tumor cells, where O(2) is deficient.
authors.affiliation: Department of Chemistry, Johns Hopkins University, Baltimore, Maryland 21218, USA.
authors.forename: In Seok
authors.initials: IS
authors.lastname: Hong
authors.forename: Hui
authors.initials: H
authors.lastname: Ding
authors.forename: Marc M
authors.initials: MM
authors.lastname: Greenberg
mesh_terms: D001483:Base Sequence; D004247:DNA / Q000737:chemistry* / Q000528:radiation effects; D003839:Deoxyadenosines / Q000737:chemistry; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000737:chemistry; D005609:Free Radicals / Q000737:chemistry; D005978:Glutathione / Q000737:chemistry; D009690:Nucleic Acid Conformation; D010100:Oxygen / Q000737:chemistry*; D010777:Photochemistry
chemical_list: D003839:Deoxyadenosines; D005609:Free Radicals; D004247:DNA; D005978:Glutathione; D010100:Oxygen; D003857:Deoxyuridine