8-hydroxyguanine and Carcinogenesis

The generation of DNA modifications in cells is in most cases accidental and associated with detrimental consequences such as increased mutation rates and an elevated risk of malignant transformation. Accordingly, repair enzymes involved in the removal of the modifications have primarily a protective function. Among the well-established exceptions of this rule are 5-methylcytosine and uracil, which are generated in DNA enzymatically under controlled conditions and fulfill important regulatory functions in DNA as epigenetic marks and in antibody diversification, respectively. More recently, considerable evidence has been obtained that also 8-oxo-7,8-dihydroguanine (8-oxoG), a frequent pro-mutagenic DNA modification generated by endogenous or exogenous reactive oxygen species (ROS), has distinct roles in the regulation of both transcription and signal transduction. Thus, the activation of transcription by the estrogen receptor, NF-κB, MYC and other transcription factors was shown to depend on the presence of 8-oxoG in the promoter regions and its recognition by the DNA repair glycosylase OGG1. The lysine-specific histone demethylase LSD1, which produces H

Topics: Animals; Carcinogenesis; DNA; DNA Glycosylases; DNA Repair; Epigenesis, Genetic; Guanine; Guanine Nucleotide Exchange Factors; Humans; Neoplasms; Oxidation-Reduction; Oxidative Stress; Risk Factors; Signal Transduction; Transcription, Genetic

Oxidatively damaged DNA results from the attack of sugar and base moieties by reactive oxygen species (ROS), which are formed as byproducts of normal cell metabolism and during exposure to endogenous or exogenous chemical or physical agents. Guanine, having the lowest redox potential, is the DNA base the most susceptible to oxidation, yielding products such as 8-oxo-7,8-dihydroguanine (8-oxoG) and 2-6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG). In DNA, 8-oxoG was shown to be mutagenic yielding GC to TA transversions upon incorporation of dAMP opposite this lesion by replicative DNA polymerases. In prokaryotic and eukaryotic cells, 8-oxoG is primarily repaired by the base excision repair pathway (BER) initiated by a DNA N-glycosylase, Fpg and OGG1, respectively. In Escherichia coli, Fpg cooperates with MutY and MutT to prevent 8-oxoG-induced mutations, the "GO-repair system". In Saccharomyces cerevisiae, OGG1 cooperates with nucleotide excision repair (NER), mismatch repair (MMR), post-replication repair (PRR) and DNA polymerase η to prevent mutagenesis. Human and mouse cells mobilize all these pathways using OGG1, MUTYH (MutY-homolog also known as MYH), MTH1 (MutT-homolog also known as NUDT1), NER, MMR, NEILs and DNA polymerases η and λ, to prevent 8-oxoG-induced mutations. In fact, mice deficient in both OGG1 and MUTYH develop cancer in different organs at adult age, which points to the critical impact of 8-oxoG repair on genetic stability in mammals. In this review, we will focus on Fpg and OGG1 proteins, their biochemical and structural properties as well as their biological roles. Other DNA N-glycosylases able to release 8-oxoG from damaged DNA in various organisms will be discussed. Finally, we will report on the role of OGG1 in human disease and the possible use of 8-oxoG DNA N-glycosylases as therapeutic targets.

Topics: Animals; Carcinogenesis; DNA Glycosylases; DNA Repair; DNA-Formamidopyrimidine Glycosylase; Escherichia coli; Escherichia coli Proteins; Genomic Instability; Guanine; Humans; Mice; Mice, Knockout; Oxidative Stress; Saccharomyces cerevisiae

8-Oxoguanine, a major oxidized base lesion formed by reactive oxygen species, causes G to T transversion mutations or leads to cell death in mammals if it accumulates in DNA. 8-Oxoguanine can originate as 8-oxo-dGTP, formed in the nucleotide pool, or by direct oxidation of the DNA guanine base. MTH1, also known as NUDT1, with 8-oxo-dGTP hydrolyzing activity, 8-oxoguanine DNA glycosylase (OGG1) an 8-oxoG DNA glycosylase, and MutY homolog (MUTYH) with adenine DNA glycosylase activity, minimize the accumulation of 8-oxoG in DNA; deficiencies in these enzymes increase spontaneous and induced tumorigenesis susceptibility. However, different tissue types have different tumorigenesis susceptibilities. These can be reversed by combined deficiencies in the defense systems, because cell death induced by accumulation of 8-oxoG in DNA is dependent on MUTYH, which can be suppressed by MTH1 and OGG1. In cancer cells encountering high oxidative stress levels, a high level of 8-oxo-dGTP accumulates in the nucleotide pool, and cells therefore express increased levels of MTH1 in order to eliminate 8-oxo-dGTP. Suppression of MTH1 may be an efficient strategy for killing cancer cells; however, because MTH1 and OGG1 protect normal tissues from oxidative-stress-induced cell death, it is important that MTH1 inhibition does not increase the risk of healthy tissue degeneration.

Topics: Animals; Carcinogenesis; Cell Survival; DNA; Guanine; Guanine Nucleotides; Humans

Oxidative stress contributes to tumourigenesis by altering gene expression. One accompanying modification, 8-oxoguanine (o

Topics: Animals; Carcinogenesis; Carcinoma, Hepatocellular; Glioma; Guanine; Liver Neoplasms; Mice; MicroRNAs; Oxidation-Reduction

Professor Barbara Tudek received the Frits Sobels Award in 2019 from the European Environmental Mutagenesis and Genomics Society (EEMGS). This article presents her outstanding character and most important lines of research. The focus of her studies covered alkylative and oxidative damage to DNA bases, in particular mutagenic and carcinogenic properties of purines with an open imidazole ring and 8-oxo-7,8-dihydroguanine (8-oxoGua). They also included analysis of mutagenic properties and pathways for the repair of DNA adducts of lipid peroxidation (LPO) products arising in large quantities during inflammation. Professor Tudek did all of this in the hope of deciphering the mechanisms of DNA damage removal, in particular by the base excision repair (BER) pathway. Some lines of research aimed at discovering factors that can modulate the activity of DNA damage repair in hope to enhance existing anti-cancer therapies. The group's ongoing research aims at deciphering the resistance mechanisms of cancer cell lines acquired following prolonged exposure to photodynamic therapy (PDT) and the possibility of re-sensitizing cells to PDT in order to increase the application of this minimally invasive therapeutic method.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Carcinogenesis; Cell Line, Tumor; DNA Adducts; DNA Damage; DNA Repair; Guanine; History, 20th Century; History, 21st Century; Humans; Lipid Peroxidation; Neoplasms; Photochemotherapy; Radiation-Sensitizing Agents

Recent studies have established that metformin (MET), an oral anti-diabetic drug, possesses antioxidant activity and is effective against different types of cancer in several carcinogen-induced animal models and cell lines. However, whether MET can protect against breast cancer has not been reported before. Therefore, the overall objectives of the present study are to elucidate the potential chemopreventive effect of MET in non-cancerous human breast MCF10A cells and explore the underlying mechanism involved, specifically the role of cytochrome P4501A1 (CYP1A1)/aryl hydrocarbon receptor (AhR) pathway. Transformation of the MCF10A cells into initiated breast cancer cells with DNA adduct formation was conducted using 7,12-dimethylbenz[a]anthracene (DMBA), an AhR ligand. The chemopreventive effect of MET against DMBA-induced breast carcinogenesis was evidenced by the capability of MET to restore the induction of the mRNA levels of basic excision repair genes, 8-oxoguanine DNA glycosylase (OGG1) and apurinic/apyrimidinic endonuclease1 (APE1), and the level of 8-hydroxy-2-deoxyguanosine (8-OHdG). Interestingly, the inhibition of DMBA-induced DNA adduct formation was associated with proportional decrease in CYP1A1 and in. quinone oxidoreductase 1 (NQO1) gene expression. Mechanistically, the involvements of AhR and nuclear factor erythroid 2-related factor-2 (Nrf2) in the MET-mediated inhibition of DMBA-induced CYP1A1 and NQO1 gene expression were evidenced by the ability of MET to inhibit DMBA-induced xenobiotic responsive element and antioxidant responsive element luciferase reporter gene expression which suggests an AhR- and Nrf2-dependent transcriptional control. However, the inability of MET to bind to AhR suggests that MET is not an AhR ligand. In conclusion, the present work shows a strong evidence that MET inhibits the DMBA-mediated carcinogenicity and adduct formation by inhibiting the expression of CYP1A1 through an AhR ligand-independent mechanism.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Breast Neoplasms; Carcinogenesis; Carcinogens; Cell Line, Tumor; Cytochrome P-450 CYP1A1; DNA Adducts; Female; Guanine; Humans; Metformin; Mice; NAD(P)H Dehydrogenase (Quinone); Receptors, Aryl Hydrocarbon; RNA, Messenger; Signal Transduction