Dou Hong, Mitra Sankar, Hazra Tapas K
Sealy Center for Molecular Science and Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas 77555, USA.
J Biol Chem. 2003 Dec 12;278(50):49679-84. doi: 10.1074/jbc.M308658200. Epub 2003 Sep 30.
Repair of oxidatively damaged bases in the genome via the base excision repair pathway is initiated with excision of these lesions by DNA glycosylases with broad substrate range. The newly discovered human DNA glycosylases, NEIL1 and NEIL2, are distinct in structural features and reaction mechanism from the previously characterized NTH1 and OGG1 but act on many of the same substrates. However, NEIL2 shows a unique preference for excising lesions from a DNA bubble, whereas NTH1 and OGG1 are only active with duplex DNA. NEIL1 also excises efficiently 5-hydroxyuracil, an oxidation product of cytosine, from the bubble and single-stranded DNA but does not have strong activity toward 8-oxoguanine in the bubble. The dichotomy in the activity of NEILs versus NTH1/OGG1 for bubble versus duplex DNA substrates is consistent with higher affinity of the NEILs for the bubble structures of both damaged and undamaged DNA relative to duplex structure. These observations suggest that the NEILs are functionally distinct from OGG1/NTH1 in vivo. OGG1/NTH1-independent repair of oxidized bases in the transcribed sequences supports the possibility that NEILs are preferentially involved in repair of lesions in DNA bubbles generated during transcription and/or replication.
通过碱基切除修复途径修复基因组中氧化损伤的碱基，是由具有广泛底物范围的DNA糖基化酶切除这些损伤来启动的。新发现的人类DNA糖基化酶NEIL1和NEIL2，在结构特征和反应机制上与先前鉴定的NTH1和OGG1不同，但作用于许多相同的底物。然而，NEIL2表现出从DNA泡中切除损伤的独特偏好，而NTH1和OGG1仅对双链DNA有活性。NEIL1也能有效地从泡状结构和单链DNA中切除胞嘧啶的氧化产物5-羟基尿嘧啶，但对泡状结构中的8-氧鸟嘌呤没有很强的活性。NEILs与NTH1/OGG1在泡状结构与双链DNA底物活性上的二分法，与NEILs相对于双链结构对受损和未受损DNA的泡状结构具有更高亲和力是一致的。这些观察结果表明，NEILs在体内与OGG1/NTH1在功能上不同。转录序列中氧化碱基的OGG1/NTH1非依赖性修复支持了这样一种可能性，即NEILs优先参与转录和/或复制过程中产生的DNA泡状结构中损伤的修复。
