Induction of OGG1 gene expression by HIV-1 tat
Induction of OGG1 gene expression by HIV-1 tat
复制标题
DOI：
10.1074/jbc.m503313200
复制
发表时间：
2005-07-22
影响因子：
4.8
通讯作者：
Okamoto, T
中科院分区：
文献类型：
--
作者：
Imai, K;Nakata, K;Okamoto, T
为了鉴定达特的细胞基因靶点，我们进行了基因表达谱分析，发现达特上调OGG 1（8-氧代鸟嘌呤-DNA糖基化酶-1）基因的表达，该基因编码一种负责修复氧化损伤的鸟苷的酶，8-氧代-7，8-二氢-2 '-脱氧鸟苷（8-氧代-dG）。我们观察到达特通过增强其启动子活性而不改变其mRNA稳定性来诱导OGG 1基因表达。我们发现，上游AP-4的OGG 1启动子的网站是负责和达特与AP-4相互作用，并删除AP-4从OGG 1启动子通过体内染色质免疫沉淀分析。因此，达特似乎通过隔离AP-4来激活OGG 1表达。有趣的是，虽然达特诱导氧化应激，已知产生8-氧代-dG，这导致G：C到T：A的颠换，我们观察到8-氧代-dG的量被达特减少。当用小干扰RNA敲除OGG 1时，达特增加了8-氧代-dG的量，从而证实了OGG 1在阻止8-氧代-dG形成中的作用。这些发现共同表明，达特可能发挥作用，通过上调OGG 1作为前馈机制的前病毒和宿主细胞基因组的遗传完整性的维护。
To identify the cellular gene target for Tat, we performed gene expression profile analysis and found that Tat up-regulates the expression of the OGG1 (8-oxoguanine-DNA glycosylase-1) gene, which encodes an enzyme responsible for repairing the oxidatively damaged guanosine, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG). We observed that Tat induced OGG1 gene expression by enhancing its promoter activity without changing its mRNA stability. We found that the upstream AP-4 site within the OGG1 promoter is responsible and that Tat interacted with AP-4 and removed AP-4 from the OGG1 promoter by in vivo chromatin immunoprecipitation assay. Thus, Tat appears to activate OGG1 expression by sequestrating AP-4. Interestingly, although Tat induces oxidative stress known to generate 8-oxo-dG, which causes the G: C to T: A transversion, we observed that the amount of 8-oxo-dG was reduced by Tat. When OGG1 was knocked down by small interfering RNA, Tat increased the amount of 8-oxo-dG, thus confirming the role of OGG1 in preventing the formation of 8-oxo-dG. These findings collectively indicate the possibility that Tat may play a role in maintenance of the genetic integrity of the proviral and host cellular genomes by upregulating OGG1 as a feed-forward mechanism.