Enzymatically inactive OGG1 binds to DNA and steers base excision repair toward gene transcription

Wenjing Hao, Jing Wang, Yuanhang Zhang, Chenxin Wang, Lan Xia, Wenhe Zhang, Muhammad Zafar, Ju Yong Kang, Ruoxi Wang, Ameer Ali Bohio, Lang Pan, Xianlu Zeng, Min Wei, Istvan Boldogh, Xueqing Ba

    Research output: Contribution to journalArticle

    Abstract

    8-Oxoguanine DNA glycosylase1 (OGG1)-initiated base excision repair (BER) is the primary pathway to remove the pre-mutagenic 8-oxo-7,8-dihydroguanine (8-oxoG) from DNA. Recent studies documented 8-oxoG serves as an epigenetic-like mark and OGG1 modulates gene expression in oxidatively stressed cells. For this new role of OGG1, two distinct mechanisms have been proposed: one is coupled to base excision, while the other only requires substrate binding of OGG1––both resulting in conformational adjustment in the adjacent DNA sequences providing access for transcription factors to their cis-elements. The present study aimed to examine if BER activity of OGG1 is required for pro-inflammatory gene expression. To this end, Ogg1/OGG1 knockout/depleted cells were transfected with constructs expressing wild-type (wt) and repair-deficient mutants of OGG1. OGG1's promoter enrichment, oxidative state, and gene expression were examined. Results showed that TNFα exposure increased levels of oxidatively modified cysteine(s) of wt OGG1 without impairing its association with promoter and facilitated gene expression. The excision deficient K249Q mutant was even a more potent activator of gene expression; whereas, mutant OGG1 with impaired substrate recognition/binding was not. These data suggested the interaction of OGG1 with its substrate at regulatory regions followed by conformational adjustment in the adjacent DNA is the primary mode to modulate inflammatory gene expression.

    Original languageEnglish (US)
    Pages (from-to)7427-7441
    Number of pages15
    JournalFASEB Journal
    Volume34
    Issue number6
    DOIs
    StatePublished - Jun 1 2020

    Keywords

    • 8-oxoG
    • OGG1
    • oxidative stress
    • pro-inflammatory gene expression

    ASJC Scopus subject areas

    • Biotechnology
    • Biochemistry
    • Molecular Biology
    • Genetics

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  • Cite this

    Hao, W., Wang, J., Zhang, Y., Wang, C., Xia, L., Zhang, W., Zafar, M., Kang, J. Y., Wang, R., Ali Bohio, A., Pan, L., Zeng, X., Wei, M., Boldogh, I., & Ba, X. (2020). Enzymatically inactive OGG1 binds to DNA and steers base excision repair toward gene transcription. FASEB Journal, 34(6), 7427-7441. https://doi.org/10.1096/fj.201902243R