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来自哺乳动物烷基腺嘌呤糖基化酶的氧化鸟嘌呤DNA糖基化酶活性。

Oxanine DNA glycosylase activity from Mammalian alkyladenine glycosylase.

作者信息

Hitchcock Thomas M, Dong Liang, Connor Ellen E, Meira Lisiane B, Samson Leona D, Wyatt Michael D, Cao Weiguo

机构信息

Department of Genetics, Biochemistry & Life Science Studies, South Carolina Experiment Station, Clemson University, Clemson, South Carolina 29634, USA.

出版信息

J Biol Chem. 2004 Sep 10;279(37):38177-83. doi: 10.1074/jbc.M405882200. Epub 2004 Jul 7.

Abstract

Oxanine (Oxa) is a deaminated base lesion derived from guanine in which the N(1)-nitrogen is substituted by oxygen. This work reports the mutagenicity of oxanine as well as oxanine DNA glycosylase (ODG) activities in mammalian systems. Using human DNA polymerase beta, deoxyoxanosine triphosphate is only incorporated opposite cytosine (Cyt). When an oxanine base is in a DNA template, Cyt is efficiently incorporated opposite the template oxanine; however, adenine and thymine are also incorporated opposite Oxa with an efficiency approximately 80% of a Cyt/Oxa (C/O) base pair. Guanine is incorporated opposite Oxa with the least efficiency, 16% compared with cytosine. ODG activity was detected in several mammalian cell extracts. Among the known human DNA glycosylases tested, human alkyladenine glycosylase (AAG) shows ODG activity, whereas hOGG1, hNEIL1, or hNEIL2 did not. ODG activity was detected in spleen cell extracts of wild type age-matched mice, but little activity was observed in that of Aag knock-out mice, confirming that the ODG activity is intrinsic to AAG. Human AAG can excise Oxa from all four Oxa-containing double-stranded base pairs, Cyt/Oxa, Thy/Oxa, Ade/Oxa, and Gua/Oxa, with no preference to base pairing. Surprisingly, AAG can remove Oxa from single-stranded Oxa-containing DNA as well. Indeed, AAG can also remove 1,N(6)-ethenoadenine from single-stranded DNA. This study extends the deaminated base glycosylase activities of AAG to oxanine; thus, AAG is a mammalian enzyme that can act on all three purine deamination bases, hypoxanthine, xanthine, and oxanine.

摘要

氧杂鸟嘌呤(Oxa)是一种由鸟嘌呤衍生而来的脱氨基碱基损伤,其中N(1)-氮被氧取代。这项工作报告了氧杂鸟嘌呤在哺乳动物系统中的致突变性以及氧杂鸟嘌呤DNA糖基化酶(ODG)活性。使用人DNA聚合酶β,脱氧氧杂鸟苷三磷酸仅在胞嘧啶(Cyt)相对位置掺入。当氧杂鸟嘌呤碱基存在于DNA模板中时,Cyt能有效地在模板氧杂鸟嘌呤相对位置掺入;然而,腺嘌呤和胸腺嘧啶也能在Oxa相对位置掺入,掺入效率约为Cyt/Oxa(C/O)碱基对的80%。鸟嘌呤在Oxa相对位置掺入的效率最低,与胞嘧啶相比为16%。在几种哺乳动物细胞提取物中检测到了ODG活性。在所测试的已知人DNA糖基化酶中,人烷基腺嘌呤糖基化酶(AAG)表现出ODG活性,而hOGG1、hNEIL1或hNEIL2则没有。在年龄匹配的野生型小鼠的脾细胞提取物中检测到了ODG活性,但在Aag基因敲除小鼠的脾细胞提取物中几乎未观察到活性,这证实了ODG活性是AAG所特有的。人AAG可以从所有四种含Oxa的双链碱基对,即Cyt/Oxa、Thy/Oxa、Ade/Oxa和Gua/Oxa中切除Oxa,对碱基配对没有偏好。令人惊讶的是,AAG也可以从含单链Oxa的DNA中去除Oxa。实际上,AAG还可以从单链DNA中去除1,N(6)-乙烯腺嘌呤。这项研究将AAG的脱氨基碱基糖基化酶活性扩展到了氧杂鸟嘌呤;因此,AAG是一种可以作用于所有三种嘌呤脱氨基碱基,即次黄嘌呤、黄嘌呤和氧杂鸟嘌呤的哺乳动物酶。

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