© 2005 Oxford University Press
DNA interstrand cross-links from modified nucleotides: mechanism and application
Johns Hopkins University, Department of Chemistry, 3400 N. Charles St., Baltimore, MD 21218, USA
Interstrand DNA cross-links are believed to be the source of cytotoxicity of antitumor agents such as mitomycin C and nitrogen mustards. We observed the first example in which DNA-DNA cross-links result from the reaction of a DNA radical. 5-(2'-Deoxyuridinyl)methyl radical (1) is produced during 
-irradiation of DNA and other methods of oxidative stress. Independent generation of this reactive intermediate in duplex DNA results in significant levels of interstrand cross-links. Cross-link formation does not require O2 and involves reaction between the nucleotide where the radical is originally generated and the opposing deoxyadenosine. Mechanistic studies have led to the identification of other molecules that produce interstrand DNA cross-links via 1. In addition, other methods for producing interstrand DNA cross-links via the radical precursor have been discovered that may be therapeutically useful.