Toxicity Inspired Cross-Linking for Probing DNA–Peptide Interactions

A cross-linking methodology for the study of DNA-protein interactions is described. The method is inspired by the metabolic activation of furans causing toxic DNA damage, including DNA-protein cross-links (DPC). The furan moiety, representing a latent functionality, is easily incorporated into oligonucleotides, and can be activated on demand to release a reactive aldehyde. Reaction with nucleophilic lysine side chains is shown to be distance-sensitive and allows for site-selective DPC formation.