Center for Integrated Protein Science at the Department of Chemistry, Ludwig Maximilians University, Munich, Germany.
Nat Chem Biol. 2013 Jul;9(7):455-61. doi: 10.1038/nchembio.1254. Epub 2013 May 19.
8-Oxopurines (8-oxodG and 8-oxodA) and formamidopyrimidines (FaPydG and FaPydA) are major oxidative DNA lesions involved in cancer development and aging. Their mutagenicity is believed to result from a conformational shift of the N9-C1' glycosidic bonds from anti to syn, which allows the lesions to form noncanonical Hoogsteen-type base pairs with incoming triphosphates during DNA replication. Here we present biochemical data and what are to our knowledge the first crystal structures of carbocyclic FaPydA and FaPydG containing DNA in complex with a high-fidelity polymerase. Crystallographic snapshots show that the cFaPy lesions keep the anti geometry of the glycosidic bond during error-free and error-prone replication. The observed dG·dC→dT·dA transversion mutations are the result of base shifting and tautomerization.
8-氧嘌呤（8-氧代-dG 和 8-氧代-dA）和酰胺嘧啶（FaPydG 和 FaPydA）是与癌症发生和衰老有关的主要氧化 DNA 损伤。它们的诱变作用被认为是由于 N9-C1' 糖苷键从反式到顺式的构象转变，这使得损伤在 DNA 复制过程中能够与进入的三磷酸形成非canonical Hoogsteen 型碱基对。在这里，我们提供了生化数据和我们所知的第一个含有高保真聚合酶的碳环 FaPydA 和 FaPydG 与 DNA 复合物的晶体结构。晶体快照表明，在无错误和易错复制过程中，cFaPy 损伤保持糖苷键的反式几何形状。观察到的 dG·dC→dT·dA 颠换突变是碱基移位和互变异构的结果。
