Oxidized Guanine Base Lesions Function in 8-Oxoguanine DNA Glycosylase-1-mediated Epigenetic Regulation of Nuclear Factor B-driven Gene Expression
Oxidized Guanine Base Lesions Function in 8-Oxoguanine DNA Glycosylase-1-mediated Epigenetic Regulation of Nuclear Factor B-driven Gene Expression
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氧化鸟嘌呤碱基损伤在 8-氧化鸟嘌呤 DNA 糖基化酶 1 介导的核因子 kappaB 驱动基因表达的表观遗传调控中发挥作用。
DOI：
10.1074/jbc.m116.751453
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发表时间：
2016-12-02
影响因子：
4.8
通讯作者：
Boldogh, Istvan
中科院分区：
文献类型：
--
作者：
Pan, Lang;Zhu, Bing;Boldogh, Istvan
大部分氧化还原反应基因启动子含有进化保守的富含鸟嘌呤的簇；鸟嘌呤是最容易受到氧化修饰的碱基。因此，7,8-二氢-8-氧代鸟嘌呤 (8-oxoG) 是启动子中最丰富的碱基损伤之一，主要通过 8-氧代鸟嘌呤 DNA 糖基化酶-1 (OOG1) 启动的碱基切除修复途径进行修复。鉴于细胞对氧化挑战的迅速反应，我们假设 8-oxoG 损伤和同源修复蛋白 OGG1 在转录基因激活中被利用。在这里，我们记录了 TNF 诱导的促炎基因启动子中 8-oxoG 和 OGG1 的富集，这发生在 NF-B 与其 DNA 结合基序相互作用之前。 OGG1 与 NF-B 基序上游的 8-oxoG 结合，通过促进 NF-B 同二聚体和异二聚体形式的结合率来增加其 DNA 占用率。 OGG1 缺失降低了 NF-B 结合和基因表达，而 Nei 样糖基化酶-1 和 -2 具有边际效应。这些结果首次记录了一种新的范例，其中与其底物结合的 DNA 修复蛋白 OGG1 与 NF-B 的 DNA 占据偶联，并在基因表达的表观遗传调控中发挥作用。
A large percentage of redox-responsive gene promoters contain evolutionarily conserved guanine-rich clusters; guanines are the bases most susceptible to oxidative modification(s). Consequently, 7,8-dihydro-8-oxoguanine (8-oxoG) is one of the most abundant base lesions in promoters and is primarily repaired via the 8-oxoguanine DNA glycosylase-1 (OOG1)-initiated base excision repair pathway. In view of a prompt cellular response to oxidative challenge, we hypothesized that the 8-oxoG lesion and the cognate repair protein OGG1 are utilized in transcriptional gene activation. Here, we document TNF-induced enrichment of both 8-oxoG and OGG1 in promoters of pro-inflammatory genes, which precedes interaction of NF-B with its DNA-binding motif. OGG1 bound to 8-oxoG upstream from the NF-B motif increased its DNA occupancy by promoting an on-rate of both homodimeric and heterodimeric forms of NF-B. OGG1 depletion decreased both NF-B binding and gene expression, whereas Nei-like glycosylase-1 and -2 had a marginal effect. These results are the first to document a novel paradigm wherein the DNA repair protein OGG1 bound to its substrate is coupled to DNA occupancy of NF-B and functions in epigenetic regulation of gene expression.