8-Oxoguanine targeted by 8-oxoguanine DNA glycosylase 1 (OGG1) is central to fibrogenic gene activation upon lung injury.
8-Oxoguanine targeted by 8-oxoguanine DNA glycosylase 1 (OGG1) is central to fibrogenic gene activation upon lung injury.
复制标题
8-氧鸟嘌呤 DNA 糖基化酶 1 (OGG1) 靶向的 8-氧鸟嘌呤对于肺损伤时纤维形成基因的激活至关重要
DOI：
10.1093/nar/gkac1241
复制
发表时间：
2023-02-22
影响因子：
14.9
通讯作者：
Boldogh, Istvan
中科院分区：
文献类型：
--
作者：
Pan, Lang;Hao, Wenjing;Xue, Yaoyao;Wang, Ke;Zheng, Xu;Luo, Jixian;Ba, Xueqing;Xiang, Yang;Qin, Xiaoqun;Bergwik, Jesper;Tanner, Lloyd;Egesten, Arne;Brasier, Allan R.;Boldogh, Istvan
摘要活性氧（ROS）参与气道损伤后上皮细胞的状态转换和细胞外基质的沉积。在ROS的许多细胞靶点中，氧化DNA修饰是主要的驱动信号。然而，氧化性DNA损伤在调节促纤维化过程中的作用尚未完全阐明。在此，我们报告，氧化DNA碱基病变，8-oxoG，与8-氧代鸟嘌呤DNA糖基化酶1（OGG 1）的功能作为一个先锋因子，有助于气道上皮细胞内的转录重编程。我们发现TGFβ1诱导的ROS增加了开放染色质中的8-oxoG水平，动态地重构了染色质状态。与8-oxoG复合的OGG 1将转录因子（包括磷酸化SMAD 3）募集至促纤维化基因启动子，从而促进基因活化。此外，在经历TGFβ1诱导的损伤的小鼠的肺中，8-oxoG水平升高。用8-oxoG结合的选择性小分子抑制剂TH 5487药理学靶向OGG 1，消除了该模型中的纤维化基因表达和重塑。总的来说，我们的研究表明，OGG 1的8-oxoG底物特异性结合是响应组织修复的转录调控的中心调节剂。
Abstract Reactive oxygen species (ROS) are implicated in epithelial cell-state transition and deposition of extracellular matrix upon airway injury. Of the many cellular targets of ROS, oxidative DNA modification is a major driving signal. However, the role of oxidative DNA damage in modulation profibrotic processes has not been fully delineated. Herein, we report that oxidative DNA base lesions, 8-oxoG, complexed with 8-oxoguanine DNA glycosylase 1 (OGG1) functions as a pioneer factor, contributing to transcriptional reprogramming within airway epithelial cells. We show that TGFβ1-induced ROS increased 8-oxoG levels in open chromatin, dynamically reconfigure the chromatin state. OGG1 complexed with 8-oxoG recruits transcription factors, including phosphorylated SMAD3, to pro-fibrotic gene promoters thereby facilitating gene activation. Moreover, 8-oxoG levels are elevated in lungs of mice subjected to TGFβ1-induced injury. Pharmacologic targeting of OGG1 with the selective small molecule inhibitor of 8-oxoG binding, TH5487, abrogates fibrotic gene expression and remodeling in this model. Collectively, our study implicates that 8-oxoG substrate-specific binding by OGG1 is a central modulator of transcriptional regulation in response to tissue repair.
登录
查看更多内容
影响因子：
7.4
作者：
Ruchko, Mykhaylo V.;Gorodnya, Olena M.;Pastukh, Viktor M.;Swiger, Brad M.;Middleton, Natavia S.;Wilson, Glenn L.;Gillespie, Mark N.
通讯作者：
Gillespie, Mark N.
影响因子：
14.9
作者：
Amente, Stefano;Di Palo, Giacomo;Majello, Barbara
通讯作者：
Majello, Barbara
酶失活的 OGG1 与 DNA 结合并引导碱基切除修复朝向基因转录
影响因子：
4.8
作者：
Hao, Wenjing;Wang, Jing;Ba, Xueqing
通讯作者：
Ba, Xueqing
影响因子：
--
作者：
Brasier, Allan R;Boldogh, Istvan
通讯作者：
Boldogh, Istvan
影响因子：
56.9
作者：
DATTA, A;JINKSROBERTSON, S
通讯作者：
JINKSROBERTSON, S