Department of Chemistry, University of California, Davis , One Shields Avenue, Davis, California 95616, United States.
J Am Chem Soc. 2013 Sep 18;135(37):13851-61. doi: 10.1021/ja4059469. Epub 2013 Sep 5.
An important feature of the common DNA oxidation product 8-oxo-7,8-dihydroguanine (OG) is its susceptibility to further oxidation that produces guanidinohydantoin (Gh) and spiroiminodihydantoin (Sp) lesions. In the presence of amines, G or OG oxidation produces hydantoin amine adducts. Such adducts may form in cells via interception of oxidized intermediates by protein-derived nucleophiles or naturally occurring amines that are tightly associated with DNA. Gh and Sp are known to be substrates for base excision repair (BER) glycosylases; however, large Sp-amine adducts would be expected to be more readily repaired by nucleotide excision repair (NER). A series of Sp adducts differing in the size of the attached amine were synthesized to evaluate the relative processing by NER and BER. The UvrABC complex excised Gh, Sp, and the Sp-amine adducts from duplex DNA, with the greatest efficiency for the largest Sp-amine adducts. The affinity of UvrA for all of the lesion duplexes was found to be similar, whereas the efficiency of UvrB loading tracked with the efficiency of UvrABC excision. In contrast, the human BER glycosylase NEIL1 exhibited robust activity for all Sp-amine adducts irrespective of size. These studies suggest that both NER and BER pathways mediate repair of a diverse set of hydantoin lesions in cells.
一种常见的 DNA 氧化产物 8-氧代-7,8-二氢鸟嘌呤（OG）的一个重要特征是其易进一步氧化，产生胍基乙内酰脲（Gh）和螺环亚氨基二氢嘧啶（Sp）损伤。在存在胺的情况下，G 或 OG 的氧化会产生尿嘧啶胺加合物。这些加合物可能通过氧化中间体与蛋白质衍生的亲核试剂或与 DNA 紧密结合的天然存在的胺的拦截而在细胞内形成。Gh 和 Sp 是碱基切除修复（BER）糖苷酶的底物；然而，大的 Sp-胺加合物预计更容易通过核苷酸切除修复（NER）修复。合成了一系列在附着的胺的大小上不同的 Sp 加合物，以评估 NER 和 BER 的相对处理。UvrABC 复合物从双链 DNA 中切除 Gh、Sp 和 Sp-胺加合物，对于最大的 Sp-胺加合物效率最高。发现 UvrA 与所有损伤双链体的亲和力相似，而 UvrB 加载的效率与 UvrABC 切除的效率相关。相比之下，人类 BER 糖苷酶 NEIL1 表现出对所有 Sp-胺加合物的强大活性，无论大小如何。这些研究表明，NER 和 BER 途径都介导了细胞中各种类型的尿嘧啶嘧啶损伤的修复。
