Efficient removal of formamidopyrimidines by 8-oxoguanine glycosylases
Efficient removal of formamidopyrimidines by 8-oxoguanine glycosylases
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DOI：
10.1021/bi701619u
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发表时间：
2008-01-22
期刊：
影响因子：
2.9
通讯作者：
David, Sheila S.
中科院分区：
文献类型：
--
作者：
Krishnamurthy, Nirmala;Haraguchi, Kazuhiro;David, Sheila S.
在氧化应激条件下，甲酰胺嘧啶损伤（FapyG 和 FapyA）是与相应的 8-氧代嘌呤（OG 和 OA）竞争从共同中间体形成的。为了揭示这些损伤修复的特征，以及修复在减轻或加剧 Fapy 损伤诱变特性方面的潜在贡献，在单周转条件下，在各种碱基对背景下检查了三种糖基酶 Fpg、hOGG1 和 Ntg1 对它们的切除。 FapyG 至少与 OG 一样被所有三种糖基化酶有效去除。此外，Fpg 和 hOGG1 去除 FapyG 的速率受到其碱基对伙伴的影响，当与正确的 Watson-Crick 伙伴 C 碱基配对时，优先去除 FapyG。对于 FapyA 损伤，Fpg 和 Ntg1 比 OG 更容易催化其去除，与所有四种天然碱基相对。相比之下，hOGG1 对 FapyA 的去除不如 FapyG 或 OG 那样强大，并且仅当病变与 C 配对时才显着。各种糖基化酶对相对碱基的区分高度依赖于病变的身份。当OG作为促诱变碱基对的一部分时，对其去除具有最大的选择性。各种 OG 糖基化酶在体外去除 FapyG 和 FapyA 的卓越活性表明这些酶可能在体内作用于这些氧化损伤。与OG相比，在非诱变与促诱变碱基对背景下，各种糖基化酶去除FapyG和FapyA的活性差异可能有助于改变这些病变的体内诱变特征。
Under conditions of oxidative stress, the formamidopyrimidine lesions (FapyG and FapyA) are formed in competition with the corresponding 8-oxopurines (OG and OA) from a common intermediate. In order to reveal features of the repair of these lesions, and the potential contribution of repair in mitigating or exacerbating the mutagenic properties of Fapy lesions, their excision by three glycosylases, Fpg, hOGG1 and Ntg1, was examined in various, base pair contexts under single-turnover conditions. FapyG was removed at least as efficiently as OG by all three glycosylases. In addition, the rates of removal of FapyG by Fpg and hOGG1 were influenced by their base pair partner, with preference for removal when base paired with the correct Watson-Crick partner C. With the FapyA lesion, Fpg and Ntg1 catalyze its removal more readily than OG opposite all four natural bases. In contrast, the removal of FapyA by hOGG1 was not as robust as FapyG or OG, and was only significant when the lesion was paired with C. The discrimination by the various glycosylases with respect to the opposing base was highly dependent on the identity of the lesion. OG induced the greatest selectivity against its removal when part of a promutagenic base pair. The superb activity of the various OG glycosylases toward removal of FapyG and FapyA in vitro suggests that these enzymes may act upon these oxidized lesions in vivo. The differences in the activity of the various glycosylases for removal of FapyG and FapyA compared to OG in nonmutagenic versus promutagenic base pair contexts may serve to alter the mutagenic profiles of these lesions in vivo.