OGG1S326C Variant Frequent in Human Populations Facilitates Inflammatory Responses Due to Its Extended Interaction With DNA Substrate

Authors

Jinling Han
Meichen Zhang
Jiakun Ge
Zhihua Ji
Jianyi Zhao
Yinchao Hu
Chunshuang Li
Yaoyao Xue
Xining Li
Haiwang Zhao
Zixu Cui
Miaomiao Tian
Xu Zheng
Dapeng Wang
Jing Wang
Min Wei
Zsolt Radak
Yusaku Nakabeppu
Istvan Boldogh
Xueqing Ba

Language

English

Publication Date

5-13-2025

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2426102122

PMID

40343995

PMCID

PMC12088383

PubMedCentral® Posted Date

5-9-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

DNA Glycosylases, Animals, Humans, Mice, DNA Repair, DNA, Inflammation, Phosphorylation, DNA Damage, NF-kappa B, Guanine, Reactive Oxygen Species, 8-oxoguanine DNA glycosylase-1 (OGG1), OGG1S326C, single nucleotide polymorphism, inflammatory gene expression, lung injury

Published Open-Access

yes

Recommended Citation

Han, Jinling; Zhang, Meichen; Ge, Jiakun; et al., "OGG1S326C Variant Frequent in Human Populations Facilitates Inflammatory Responses Due to Its Extended Interaction With DNA Substrate" (2025). Faculty, Staff and Student Publications. 6629.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6629