8-OxoG in GC-rich Sp1 binding sites enhances gene transcription in adipose tissue of juvenile mice

Park, Jong Woo; Han, Young In; Kim, Sung Woo; Kim, Tae Min; Yeom, Su Cheong; Kang, Jaeku; Park, Joonghoon

doi:10.1038/s41598-019-52139-z

Cited by 14 publications

(16 citation statements)

References 45 publications

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“…Due to its propensity to mispair with adenines during replication, unrepaired guanine lesions can lead to mutagenesis and cellular transformation [ 1 , 2 , 3 , 4 ]. Furthermore, the presence of oxidized guanines in GC-rich promoter regions have been implicated in altering gene transcription, thereby impacting cellular function [ 5 , 6 , 7 , 8 ]. 8-oxoG is primarily excised by the base excision repair (BER) glycosylase OGG1, which localizes to both the nucleus and mitochondria [ 9 , 10 , 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

A Novel Role for the DNA Repair Enzyme 8-Oxoguanine DNA Glycosylase in Adipogenesis

Komakula

Blaze

et al. 2021

IJMS

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Cells sustain constant oxidative stress from both exogenous and endogenous sources. When unmitigated by antioxidant defenses, reactive oxygen species damage cellular macromolecules, including DNA. Oxidative lesions in both nuclear and mitochondrial DNA are repaired via the base excision repair (BER) pathway, initiated by DNA glycosylases. We have previously demonstrated that the BER glycosylase 8-oxoguanine DNA glycosylase (OGG1) plays a novel role in body weight maintenance and regulation of adiposity. Specifically, mice lacking OGG1 (Ogg1−/−) are prone to increased fat accumulation with age and consumption of hypercaloric diets. Conversely, transgenic animals with mitochondrially-targeted overexpression of OGG1 (Ogg1Tg) are resistant to age- and diet-induced obesity. Given these phenotypes of altered adiposity in the context of OGG1 genotype, we sought to determine if OGG1 plays a cell-intrinsic role in adipocyte maturation and lipid accumulation. Here, we report that preadipocytes from Ogg1−/− mice differentiate more efficiently and accumulate more lipids than those from wild-type animals. Conversely, OGG1 overexpression significantly blunts adipogenic differentiation and lipid accretion in both pre-adipocytes from Ogg1Tg mice, as well as in 3T3-L1 cells with adenovirus-mediated OGG1 overexpression. Mechanistically, changes in adipogenesis are accompanied by significant alterations in cellular PARylation, corresponding with OGG1 genotype. Specifically, deletion of OGG1 reduces protein PARylation, concomitant with increased adipogenic differentiation, while OGG1 overexpression significantly increases PARylation and blunts adipogenesis. Collectively, these data indicate a novel role for OGG1 in modulating adipocyte differentiation and lipid accretion. These findings have important implications to our knowledge of the fundamental process of adipocyte differentiation, as well as to our understanding of lipid-related diseases such as obesity.

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Section: Introductionmentioning

confidence: 99%

A Novel Role for the DNA Repair Enzyme 8-Oxoguanine DNA Glycosylase in Adipogenesis

Komakula

Blaze

et al. 2021

IJMS

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“…The discovery of a highly conserved pattern of distribution of 8-oxodG in the genome suggested a non-stochastic character of the damage generation or/and variable repair efficiencies along human chromosomes [ 10 ]. Recent advances in the whole-genome sequencing techniques allowed a higher resolution mapping of 8-oxodG over the genomes of various organisms which revealed highly heterogeneous 8-oxodG distribution patterns [ [11] , [12] , [13] , [14] , [15] , [16] ]. Intriguingly, 8-oxodG clustering in the specific chromosomal regions showed pronounced correlations with both chromatin organisation [ 11 , 12 ] and functions of the identified genome elements in DNA replication and transcription [ [12] , [13] , [14] , [15] , [16] ].…”

Section: Introductionmentioning

confidence: 99%

“…Recent advances in the whole-genome sequencing techniques allowed a higher resolution mapping of 8-oxodG over the genomes of various organisms which revealed highly heterogeneous 8-oxodG distribution patterns [ [11] , [12] , [13] , [14] , [15] , [16] ]. Intriguingly, 8-oxodG clustering in the specific chromosomal regions showed pronounced correlations with both chromatin organisation [ 11 , 12 ] and functions of the identified genome elements in DNA replication and transcription [ [12] , [13] , [14] , [15] , [16] ]. The observations of sharp 8-oxodG distribution patterns corroborate the notion that, at least, some portion of genomic 8-oxodG might be generated in a regulated fashion and that the abundance of this DNA modification at particular genomic loci is controlled by differential DNA repair [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Regulation of GC box activity by 8-oxoguanine

Müller

Khobta

2021

Redox Biology

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The oxidation-induced DNA modification 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) was recently implicated in the activation and repression of gene transcription. We aimed at a systematic characterisation of the impacts of 8-oxodG on the activity of a GC box placed upstream from the RNA polymerase II core promoter. With the help of reporters carrying single synthetic 8-oxodG residues at four conserved G:C base pairs (underlined) within the 5′-TG GGCG GAGC-3′ GC box sequence, we identified two modes of interference of 8-oxodG with the promoter activity. Firstly, 8-oxodG in the purine-rich (but not in the pyrimidine-rich) strand caused direct impairment of transcriptional activation. In addition, and independently of the first mechanism, 8-oxodG initiated a decline of the gene expression, which was mediated by the specific DNA glycosylase OGG1. For the different 8-oxodG positions, the magnitude of this effect reflected the excision preferences of OGG1. Thus, 8-oxodG seeded in the pyrimidine-rich strand was excised with the highest efficiency and caused the most pronounced decrease of the promoter activity. Conversely, 8-oxodG in the symmetric position within the same CpG dinucleotide, was poorly excised and induced no decline of the gene expression. Of note, abasic lesions caused gene silencing in both positions. By contrast, an uncleavable apurinic lesion in the pyrimidine-rich strand enhanced the GC box activity, suggesting that the AP endonuclease step provides a switch between the active versus repressed promoter states during base excision repair.

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“…Research has yet to determine how the activity of these genes is regulated by 8-oxoG lesions caused by oxidative stress. Considering the regulation of gene activity through the deletion of the corresponding genomic loci by 8-oxoG or the epigenetic function of 8-oxoG [ 32 , 33 , 34 ], subsequent studies on these subjects would be valuable for a genetic understanding of the impairment of spermatogenesis caused by oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

“…Genomic DNA was extracted from sperm, using the DNeasy Blood and Tissue kit (Qiagen, Valencia, CA, USA) with supplementation of desferal and butylated hydroxytoluene at 100 µM each (Sigma-Aldrich, St. Louis, MO, USA). The extracted DNA was enzymatically hydrolyzed as previously described [ 34 ]. 8-[15N5]oxoG at 10 nM was used as a spike control (Cambridge Isotope Laboratories, Inc., Tewksbury, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

Dysregulation of the Acrosome Formation Network by 8-oxoguanine (8-oxoG) in Infertile Sperm: A Case Report with Advanced Techniques

Kim

Mok

et al. 2021

IJMS

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8-Hydroxyguanine (8-oxoG) is the most common oxidative DNA lesion and unrepaired 8-oxoG is associated with DNA fragmentation in sperm. However, the molecular effects of 8-oxoG on spermatogenesis are not entirely understood. Here, we identified one infertile bull (C14) due to asthenoteratozoospermia. We compared the global concentration of 8-oxoG by reverse-phase liquid chromatography/mass spectrometry (RP-LC/MS), the genomic distribution of 8-oxoG by next-generation sequencing (OG-seq), and the expression of sperm proteins by 2-dimensional polyacrylamide gel electrophoresis followed by peptide mass fingerprinting (2D-PAGE/PMF) in the sperm of C14 with those of a fertile bull (C13). We found that the average levels of 8-oxoG in C13 and C14 sperm were 0.027% and 0.044% of the total dG and it was significantly greater in infertile sperm DNA (p = 0.0028). Over 81% of the 8-oxoG loci were distributed around the transcription start site (TSS) and 165 genes harboring 8-oxoG were exclusive to infertile sperm. Functional enrichment and network analysis revealed that the Golgi apparatus was significantly enriched with the products from 8-oxoG genes of infertile sperm (q = 2.2 × 10-7). Proteomic analysis verified that acrosome-related proteins, including acrosin-binding protein (ACRBP), were downregulated in infertile sperm. These preliminary results suggest that 8-oxoG formation during spermatogenesis dysregulated the acrosome-related gene network, causing structural and functional defects of sperm and leading to infertility.

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8-OxoG in GC-rich Sp1 binding sites enhances gene transcription in adipose tissue of juvenile mice

Cited by 14 publications

References 45 publications

A Novel Role for the DNA Repair Enzyme 8-Oxoguanine DNA Glycosylase in Adipogenesis

A Novel Role for the DNA Repair Enzyme 8-Oxoguanine DNA Glycosylase in Adipogenesis

Regulation of GC box activity by 8-oxoguanine

Dysregulation of the Acrosome Formation Network by 8-oxoguanine (8-oxoG) in Infertile Sperm: A Case Report with Advanced Techniques

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