Substrate-specific binding of 8-oxoguanine DNA glycosylase 1 (OGG1) reprograms mucosal adaptations to chronic airway injury

Pan, Lang; Vlahopoulos, Spiros; Tanner, Lloyd; Bergwik, Jesper; Bácsi, Attila; Radák, Zsolt; Egesten, Arne; Ba, Xueqing; Brasier, Allan R.; Boldogh, István

doi:10.3389/fimmu.2023.1186369

Cited by 4 publications

(3 citation statements)

References 116 publications

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“…Additionally, it was shown that DNA-bound OGG1 at 8-oxoGua interacted with mitogen-and stress-activated kinase 1, which phosphorylates NFκB/RelA at serine 276, inducing expression of innate cytokines and chemokines [ 46 ]. A recent study documented that OGG1 at 8-oxoGua in the context of chromatin recruited phosphorylated SMAD2/3 complex and NFκB to their cognate binding sequence located in promoters of tissue remodeling genes including alpha-smooth muscle actin (α-SMA), collagen (COL), and fibronectin (FN) for excessive gene expression [ 41 , 47 ]. Another recent study revealed that Myc oncogene binding to the E-box promoter recognition sequence required OGG1 under oxidative stress conditions [ 48 ].…”

Section: Ogg1 Induces Dna Remodeling In Proximity Of Transacting Fact...mentioning

confidence: 99%

“…Exposure of cells to increased oxidative stress provides a powerful stimulus to NFκB-driven gene regulation [ 75 ]. This is exemplified by NFκB interaction with OGG1 [ 35 , 47 , 76 ], which redirects NFκB activity and impairs immunity [ 76 ]. In contrast, enzymatically active OGG1 guards genome integrity through either lesion repair or elimination of cells with malignant potential, to maintain the homeostasis of the host, which might depend on the magnitude of guanine oxidation [ 77 ].…”

Section: Oxidative Stress As a Driver For Cancer Plasticitymentioning

confidence: 99%

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OGG1 as an Epigenetic Reader Affects NFκB: What This Means for Cancer

Vlahopoulos,

Pan,

Varisli

et al. 2023

Cancers

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8-oxoguanine glycosylase 1 (OGG1), which was initially identified as the enzyme that catalyzes the first step in the DNA base excision repair pathway, is now also recognized as a modulator of gene expression. What is important for cancer is that OGG1 acts as a modulator of NFκB-driven gene expression. Specifically, oxidant stress in the cell transiently halts enzymatic activity of substrate-bound OGG1. The stalled OGG1 facilitates DNA binding of transactivators, such as NFκB to their cognate sites, enabling the expression of cytokines and chemokines, with ensuing recruitment of inflammatory cells. Recently, we highlighted chief aspects of OGG1 involvement in regulation of gene expression, which hold significance in lung cancer development. However, OGG1 has also been implicated in the molecular underpinning of acute myeloid leukemia. This review analyzes and discusses how these cells adapt through redox-modulated intricate connections, via interaction of OGG1 with NFκB, which provides malignant cells with alternative molecular pathways to transform their microenvironment, enabling adjustment, promoting cell proliferation, metastasis, and evading killing by therapeutic agents.

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Section: Ogg1 Induces Dna Remodeling In Proximity Of Transacting Fact...mentioning

confidence: 99%

Section: Oxidative Stress As a Driver For Cancer Plasticitymentioning

confidence: 99%

OGG1 as an Epigenetic Reader Affects NFκB: What This Means for Cancer

Vlahopoulos,

Pan,

Varisli

et al. 2023

Cancers

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“…As such, the 8-oxoG chemical modification has garnered interest for study as a biomarker of oxidative stress. In human DNA, 8-oxodG damage is corrected by the base excision repair protein, 8-oxoguanine DNA glycosylase (OGG1) [19][20][21]. However, despite RNA being more susceptible to oxidative damage than DNA [22,23], such a mechanism for oxidative damage repair in human RNA remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Optimized chemical labeling method for isolation of 8-oxoG-modified RNA, ChLoRox-Seq, identifies mRNAs enriched in oxidation and transcriptome-wide distribution biases of oxidation events post environmental stress

Burroughs,

Sweet,

Contreras

2024

Preprint

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Bulk increases in nucleobase oxidation, most commonly manifesting as the guanine (G) nucleobase modification 8-oxo-7,8-dihydroguanine (8-oxoG), have been linked to several disease pathologies. Elucidating the effects of RNA oxidation on cellular homeostasis is limited by a lack of effective tools for detecting specific regions modified with 8-oxoG. Building on a previously published method for studying 8-oxoG in DNA, we developed ChLoRox-Seq, which works by covalently functionalizing 8-oxoG sites in RNA with biotin. Importantly, this method enables antibody-free enrichment of 8-oxoG-containing RNA fragments for Next Generation Sequencing-based detection of modified regions transcriptome-wide. We demonstrate the high specificity of ChLoRox-Seq for functionalizing 8-oxoG over unmodified nucleobases in RNA and benchmark this specificity to a commonly used antibody-based approach. Key advantages of ChLoRox-Seq include: (1) heightened resolution of RNA oxidation regions (e.g. exon-level) and (2) lower experimental costs. By applying ChLoRox-Seq to mRNA extracted from human lung epithelial cells (BEAS-2B) after exposure to environmentally relevant stress, we observe that 8-oxoG modifications tend to cluster in regions that are G-rich and within mRNA transcripts possessing longer 5’ UTR and CDS regions. These findings provide new insight into the complex mechanisms that bias the accumulation of RNA oxidation across the transcriptome. Notably, our analysis suggests the possibility that most mRNA oxidation events are probabilistically driven and that mRNAs that possess more favorable intrinsic properties are prone to incur oxidation events at elevated rates. ChLoRox-Seq can be readily applied in future studies to identify regions of elevated RNA oxidation in any cellular model of interest.

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