活性氧可引起体内各种生物大分子的氧化，其中DNA碱基是主要作用靶点之一，鸟嘌呤因其氧还电势最低而极易被氧化，形成的损伤产物8-羟鸟嘌呤被认为与多种疾病发生高度相关，但直接实验证据却极度缺乏。我们前期工作发现8-羟鸟嘌呤修复酶OGG1与含有8-羟鸟嘌呤的高GC含量启动子结合后，促进了转录因子NF-kB的招募及活性氧信号依赖的促炎基因转录活化，但DNA损伤修复酶OGG1如何影响基因转录的分子机制尚未深入揭示。本项目研究将利用二代测序技术及蛋白-蛋白、蛋白-核酸作用分析技术深入解析1)全基因组范围内OGG1、NF-kB的染色质免疫沉淀组、OGG1依赖的转录组的关联性及高度代表基因的功能2)OGG1与NF-kB相互作用的分子机制3)OGG1与NF-kB相互作用对启动子区序列环境的要求。项目的完成将揭示DNA修复酶OGG1转录活化的新功能及NF-kB活性调节的新机制，为炎症相关疾病的治疗提供新的靶点

Reactive oxygen species (ROS) may inflict oxidation modification to various bio-macromolecules including DNA bases. Among 4 DNA bases guanine is the most frequent targetdue to its lowest redox potential, and its oxidized product,7,8-dihydro-8-oxoguanine (8-oxoG), is linked to the pathogenesis of many diseases despite of the lack of direct experimental evidence. It has been reported that depletion of 8-oxoG glycosylase 1 (OGG1), the specific enzyme to repair 8-oxoG lesion in DNA duplex, resulted in the significant decrease of pro-inflammatory geneexpression which are highly ROS signaling-dependent. Our recent publication also documented that OGG1 binds to 8-oxoG within high GC-containing promoters, facilitates the recruitment of site specific transcription factors such as NF-κB, as well as the transcription of pro-inflammatory genes. This unexpected finding urged us to further explore the precise molecular mechanisms how a DNA repair enzyme regulates gene transcription. In the proposed study, we will utilize next generation sequencing skills such as ChIP-Seq, RNA-Seq, as well as various molecular techniques analyzing the interaction between protein-protein and protein-DNA, to define 1) in a whole genome scale, the characters of the binding sites of OGG1 and NF-κB, the transcriptome associated with OGG1 expression as well as the gene ontology annotation and the related pathways revealed by the omics data;2)the precise molecular mechanisms by which OGG1 interacts with NF-κB; 3) the DNA sequence context within the high GC-containing promoters that is required for the OGG1- NF-κB complex-driven transcription. The completion of the proposed study will add insight to the role of DNA repair enzyme OGG1 in gene transcription initiation; unveil a novel mechanism by which NF-κB achieves sophisticated regulation under oxidative stress. More importantly, the structural resolution of the interaction of OGG1- NF-κB complex will benefit the design of inhibitory small compounds that may be utilized in the intervention of chronic inflammatory diseases.