Toxicity and repair of DNA adducts produced by the natural product yatakemycin

Yatakemycin (YTM) is an extraordinarily toxic DNA alkylating agent with potent antimicrobial and antitumor properties and the most recent addition to the CC-1065 and duocarmycin family of natural products. While bulky DNA lesions the size of those produced by YTM are normally removed from the genome by the nucleotide excision repair (NER) pathway, YTM adducts are also a substrate for the bacterial DNA glycosylases AlkD and YtkR2, unexpectedly implicating base excision repair (BER) in their elimination. The reason for the extreme toxicity of these lesions and the molecular basis for how they are eliminated by BER have been unclear. Here, we describe the structural and biochemical properties of YTM adducts responsible for their toxicity, and define the mechanism by which they are excised by AlkD. These findings delineate an alternative strategy for repair of bulky DNA damage and establish the cellular utility of this pathway relative to that of NER.