DNA糖苷酶OGG1调节PARP1介导的EB病毒潜伏蛋白表达的机制研究

批准号:
32000546
项目类别:
青年科学基金项目
资助金额:
24.0 万元
负责人:
郝文静
依托单位:
学科分类:
细胞信号转导
结题年份:
2023
批准年份:
2020
项目状态:
已结题
项目参与者:
郝文静
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中文摘要
EB病毒(EBV)潜伏相关基因表达是潜在的致瘤因素。EBV感染导致氧化应激,宿主及病毒基因组产生大量的8-羟鸟嘌呤;其特异性修复酶OGG1表达升高,有利于EBV潜伏感染,但机制尚不清楚。研究表明,PARP1在Cp启动子的募集和活化促进EBV潜伏基因全部表达。但PARP1选择性结合在Cp启动子及所需核苷酸环境机制仍需深入探究。我们的前期数据显示,OGG1促进EBNA1的转录及PARP1的PAR化修饰。本项目将利用ChIP-seq、蛋白-蛋白/核酸作用及双荧光素酶报告系统等技术,深入解析:1)OGG1调节EBV潜伏相关蛋白表达是否依赖其糖苷酶活性;2)OGG1调节Cp启动子活性的分子机制;3)OGG1与PARP1相互作用驱动EBV潜伏基因转录的启动子活化所依赖8-oxoG的序列环境特征。项目的完成将明晰OGG1促进EBV潜伏感染的分子机制,为EBV潜伏感染及相关肿瘤发生的阻断提供新的潜在靶点。
英文摘要
The EB viral latency type-specific gene expression is potentially oncogenic for some human cancers. During EBV infection, both the host and virus suffer oxidative stress cause abundant 8-hydroxyguanine (8-oxoG) in their genome and result in 8-oxoguanine glycosylase1 (OGG1) highly expressed, which is benefit for EBV latent infection, but the mechanism is unknown, either. From recent publications, the recruitment and activation of host enzyme poly(ADP-ribose) polymerase 1(PARP1) in the Cp promoter promotes EBV latent infection and its full repertoire of latent proteins are expressed. However, the modulate mechanism of PARP1 selectively binds to the Cp promoter is unclear and the sequences characteristics of the binding region is still to investigate elaborately. Our previously data indicated that OGG1 could promote transcription of EBV nuclear antigen 1 (EBNA1) and PARP1 modification as PARylation. In this proposed study, we will employ ChIP-Seq, Co-IP, EMSA and dual reporter assay (Firefly/Renilla luciferases) to determine: 1) Whether OGG1 regulates the expression of EBV latent proteins depends on its glycosidase cleavage activity; 2) the molecular mechanism of OGG1 interacting with PARP1 to regulate Cp promoter activity; and 3) the sequences characteristics of the promoter region in EBV genome that 8-oxoG produced required for OGG1 interacts with PARP1 to drive EBV latency gene transcription. Obviously, the completion of the project would clarify the molecular mechanism of OGG1 promoting EBV latency infection, as well as reveal potential targets for the treatment of EBV infection and intervention in EBV-associated cancers.
期刊论文列表
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科研奖励列表
会议论文列表
专利列表
8-Oxoguanine targeted by 8-oxoguanine DNA glycosylase 1 (OGG1) is central to fibrogenic gene activation upon lung injury.
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
发表时间:2023-02-22
期刊:NUCLEIC ACIDS RESEARCH
影响因子:14.9
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
通讯作者:Boldogh, Istvan
DOI:10.1016/j.jbc.2023.105308.
发表时间:2023
期刊:J Biol Chem .
影响因子:--
作者:Yaoyao Xue;Chunshuang Li;Shihua Deng;Xin Chen;Jinling Han;Xu Zheng;Miaomiao Tian;Wenjing Hao;Lang Pan;Istvan Boldogh;Xueqing Ba;Ruoxi Wang
通讯作者:Ruoxi Wang
国内基金
海外基金
