Yatakemycin (YTM) is an extraordinarily toxic DNA alkylating agent with potent antimicrobial and antitumor properties and is the most recent addition to the CC-1065 and duocarmycin family of natural products. Though 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 the way they are eliminated by BER have been unclear. Here, we describe the structural and biochemical properties of YTM adducts that are 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.

中文翻译：

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天然产品yatakemycin产生的DNA加合物的毒性和修复

Yatakemycin（YTM）是一种具有极强毒性的DNA烷基化剂，具有强大的抗菌和抗肿瘤特性，是CC-1065和duocarmycin系列天然产物的最新成员。虽然通常通过核苷酸切除修复（NER）途径从基因组中去除了基因组中体积庞大的DNA损伤，但YTM加合物还是细菌DNA糖基化酶AlkD和YtkR2的底物，出乎意料地牵涉碱基切除修复（ BER）。这些病变具有极高毒性的原因以及通过BER消除这些病变的分子基础尚不清楚。在这里，我们描述了负责其毒性的YTM加合物的结构和生化特性，并定义了AlkD切除它们的机理。