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Base Excision Repair of Bulky DNA Adducts Generated by the Antitumor Drug Yatakemycin

Threats to genomic integrity are mitigated by DNA glycosylases, which initiate the base excision repair pathway by locating and excising aberrant nucleobases. A hallmark of these and other DNA repair enzymes is their use of base flipping to sequester modified nucleotides from the DNA helix and into an active site pocket. Consequently, base flipping is generally regarded as an essential aspect of lesion recognition and a necessary precursor to base excision. We recently described the first DNA glycosylase mechanism that does not require base flipping for either binding or catalysis1. The DNA glycosylase AlkD recognizes aberrant base pairs through contacts with the phosphoribose backbone, while the damaged nucleobase remains stacked in the DNA duplex, and and uses catalytic CH–π and charge–dipole interactions to preferentially stabilize the transition state. We now show through a combination of crystallographic, biochemical, biophysical, and cellular techniques how this unique mechanism enables AlkD to repair large adducts formed by yatakemycin (Fig. 1), a member of the duocarmycin and CC‐1065 family of antimicrobial and antitumor natural products. Bulky adducts of this, or any type, are not excised by DNA glycosylases that use a traditional base‐flipping mechanism. Hence, these findings represent a new paradigm for DNA repair and provide insights into damage recognition and base excision.