OGG1S326C variant frequent in human populations facilitates inflammatory responses due to its extended interaction with DNA substrate
Abstract
8-oxoguanine (8-oxoGua) is one of the most frequent forms of oxidative DNA base lesions, repaired by 8-oxoguanine DNA glycosylase 1 (OGG1) via base excision repair (BER) pathway to maintain genome fidelity. The human allelic variant hOGG1 S326C , prevalent in Caucasians and Asians, has been regarded as a susceptibility factor for various diseases, yet its pathogenic mechanism remains elusive. In this study, we demonstrate that Ogg1 S326C/S326C mice exhibit increased and sustained airway inflammation compared with wild-type (WT) Ogg1 S326/S326 mice. Mechanistically, in response to inflammatory stimulation, OGG1S326C undergoes reactive oxygen species-induced dimerization, which impairs its base excision function, but prolongs its association with promoter-embedded substrate(s), leading to an increase in NF-κB’ DNA occupancy, subsequently the excessive expression of proinflammatory cytokines and chemokines, and the exacerbated lung inflammation. In contrast, Serine at position 326 in WT -OGG1 is constitutively phosphorylated by CDK4. To fulfill the requirement for its function in transcriptional regulation, the phosphorylated OGG1 needs to undergo dephosphorylation to rescue DNA binding ability. In this scenario, OGG1S326C lacks this phosphorylation site, disrupting this regulatory cycle. Notably, administration of a small molecule inhibitor of OGG1 prevents OGG1S326C from binding to DNA and significantly decreases gene expression and inflammatory responses. Our findings elucidate a molecular basis for the increased disease susceptibility of individuals carrying the hOGG1 S326C variant and propose the therapeutic potential of OGG1 inhibitors in mitigating inflammation-driven pathologies.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (20)
Jinling Han
Division of Human Health, Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University
Meichen Zhang
Division of Human Health, Key Laboratory of Molecular Epigenetics of Ministry of Education, Northeast Normal University
Jiakun Ge
Division of Human Health, Key Laboratory of Molecular Epigenetics of Ministry of Education, Northeast Normal University
Zhihua Ji
Division of Human Health, Key Laboratory of Molecular Epigenetics of Ministry of Education, Northeast Normal University
Jianyi Zhao
Department of Respiratory Medicine, China-Japan Union Hospital of Jilin University
Yinchao Hu
Division of Human Health, Key Laboratory of Molecular Epigenetics of Ministry of Education, Northeast Normal University
Chunshuang Li
Division of Human Health, Key Laboratory of Molecular Epigenetics of Ministry of Education, Northeast Normal University
Yaoyao Xue
Division of Human Health, Key Laboratory of Molecular Epigenetics of Ministry of Education, Northeast Normal University
Xining Li
Division of Human Health, Key Laboratory of Molecular Epigenetics of Ministry of Education, Northeast Normal University
Haiwang Zhao
Division of Human Health, Key Laboratory of Molecular Epigenetics of Ministry of Education, Northeast Normal University
Zixu Cui
Division of Human Health, Key Laboratory of Molecular Epigenetics of Ministry of Education, Northeast Normal University
Miaomiao Tian
Division of Human Health, Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University
Xu Zheng
Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University
Dapeng Wang
Jing Wang
Hunan Cancer Hospital Changsha China
Min Wei
Department of Chemistry and Key Laboratory for Preparation and Application of Ordered Structural Materials of Guangdong Province
Zsolt Radak
Research Center for Molecular Exercise Science, Institute of Sport Science, University of Physical Education
Yusaku Nakabeppu
Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University
Istvan Boldogh
Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston
Xueqing Ba