Oxygen independent DNA interstrand cross-link formation by a nucleotide radical.
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.
Hong
In Seok
IS
Department of Chemistry, Johns Hopkins University, Baltimore, Maryland 21218, USA.
Ding
Hui
H
Greenberg
Marc M
MM
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
D003839:Deoxyadenosines; D005609:Free Radicals; D004247:DNA; D005978:Glutathione; D010100:Oxygen; D003857:Deoxyuridine