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Chembiochem : a European Journal of... Apr 2021RNA molecules can fold into complex two- and three-dimensional shapes that are critical for their function. Chemical probes have long been utilized to interrogate RNA... (Review)
Review
RNA molecules can fold into complex two- and three-dimensional shapes that are critical for their function. Chemical probes have long been utilized to interrogate RNA structure and are now considered invaluable resources in the goal of relating structure to function. Recently, the power of deep sequencing and careful chemical probe design have merged, permitting researchers to obtain a holistic understanding of how RNA structure can be utilized to control RNA biology transcriptome-wide. Within this review, we outline the recent advancements in chemical probe design for interrogating RNA structures inside cells and discuss the recent advances in our understanding of RNA biology through the lens of chemical probing.
Topics: DNA Adducts; DNA, Complementary; Molecular Probes; Nucleic Acid Conformation; RNA; RNA, Messenger; Transcriptome
PubMed: 32737940
DOI: 10.1002/cbic.202000340 -
Scientific Reports Oct 2023To further explore the pharmacological effect of pachymaran, this article studied the inhibition of pachymaran on oxidative stress and genetic damage induced by...
To further explore the pharmacological effect of pachymaran, this article studied the inhibition of pachymaran on oxidative stress and genetic damage induced by formaldehyde. 40 adult Kunming male mice were randomly divided into four groups with different interventions. One week later, the contents of serum SOD, GR, MDA, DNA-protein crosslink (DPC), 8-hydroxydeoxyguanosine (8-OHDG) and DNA adduct were determined by ELISA. The results showed that there were statistically significant differences in the contents of SOD, GR and MDA among the four groups (P < 0.01). The activity of SOD and GR increased along with the increase of pachymaran dosage (SOD: r = 0.912, P < 0.01; GR: r = 0.857, P < 0.01), while the content of MDA showing a significant negative correlation (r = - 0.893, P < 0.01). There were statistically significant differences in the levels of DPC, 8-OHDG and DNA adduct among the four groups (DPC and DNA adduct: P < 0.01, 8-OHDG: P < 0.05), the concentration decreased along with the increase of pachymaran dosage (DPC: r = - 0.855, P < 0.01; 8-OHDG:r = - 0.412, P < 0.05, DNA adduct: γ = - 0.869, P < 0.01). It can be inferred that pachymaran can inhibit oxidative stress and DNA damage induced by formaldehyde with the dose-effect relationship.
Topics: Mice; Animals; Male; DNA Adducts; 8-Hydroxy-2'-Deoxyguanosine; DNA Damage; Oxidative Stress; Formaldehyde; Proteins; Superoxide Dismutase; Deoxyguanosine
PubMed: 37838763
DOI: 10.1038/s41598-023-44788-y -
Chemical Research in Toxicology Dec 2020Chemically induced DNA adducts can lead to mutations and cancer. Unfortunately, because common analytical methods (e.g., liquid chromatography-mass spectrometry) require...
Chemically induced DNA adducts can lead to mutations and cancer. Unfortunately, because common analytical methods (e.g., liquid chromatography-mass spectrometry) require adducts to be digested or liberated from DNA before quantification, information about their positions within the DNA sequence is lost. Advances in nanopore sequencing technologies allow individual DNA molecules to be analyzed at single-nucleobase resolution, enabling us to study the dynamic of epigenetic modifications and exposure-induced DNA adducts in their native forms on the DNA strand. We applied and evaluated the commercially available Oxford Nanopore Technology (ONT) sequencing platform for site-specific detection of DNA adducts and for distinguishing individual alkylated DNA adducts. Using ONT and the publicly available ELIGOS software, we analyzed a library of 15 plasmids containing site-specifically inserted - or -alkyl-2'-deoxyguanosine lesions differing in sizes and regiochemistries. Positions of DNA adducts were correctly located, and individual DNA adducts were clearly distinguished from each other.
Topics: DNA; DNA Adducts; Molecular Structure; Nanopore Sequencing; Particle Size; Plasmids; Stereoisomerism; Surface Properties
PubMed: 32799528
DOI: 10.1021/acs.chemrestox.0c00202 -
International Journal of Occupational... Mar 2017The role of glutathione S-transferase Mu 1 (GSTM1) in the biomonitoring of polycyclic aromatic hydrocarbons (PAHs) is not clear. Our purpose has been to evaluate the... (Meta-Analysis)
Meta-Analysis Review
The role of glutathione S-transferase Mu 1 (GSTM1) in the biomonitoring of polycyclic aromatic hydrocarbons (PAHs) is not clear. Our purpose has been to evaluate the influence of GSTM1 genotypes on 1-hydroxypyrene (1-OHP), deoxyribonucleic acid (DNA) adducts, and micronucleus frequency in both occupational and non-occupational populations of null and active GSTM1 carriers. We conducted a meta-analysis on 25 articles that met our strict inclusion criteria (11 studies on 1-OHP, 9 on DNA adducts, and 5 on the micronucleus frequency). In the case of occupationally exposed workers, micronucleus frequency was only significantly higher in the null GSTM1 carriers than in the active GSTM1 carriers. In the non-occupationally exposed general population, 1-OHP and micronucleus frequency were significantly higher in the null GSTM1 carriers. The results of Egger's test and funnel plot analysis indicated no significant publication bias. In conclusion, GSTM1 genotypes may affect the urinary 1-OHP in the non-occupationally exposed general population, and micronucleus frequency in both occupational workers and non-occupational population. Int J Occup Med Environ Health 2017;30(2):177-201.
Topics: Biomarkers; DNA Adducts; Female; Glutathione Transferase; Humans; Male; Occupational Exposure; Polycyclic Aromatic Hydrocarbons; Polymorphism, Genetic; Pyrenes
PubMed: 28366950
DOI: 10.13075/ijomeh.1896.01054 -
Chemical Research in Toxicology Jan 2022Cancer remains the second most frequent cause of death in human populations worldwide, which has been reflected in the emphasis placed on management of risk from... (Review)
Review
Cancer remains the second most frequent cause of death in human populations worldwide, which has been reflected in the emphasis placed on management of risk from environmental chemicals considered to be potential human carcinogens. The formation of DNA adducts has been considered as one of the key events of cancer, and persistence and/or failure of repair of these adducts may lead to mutation, thus initiating cancer. Some chemical carcinogens can produce DNA adducts, and DNA adducts have been used as biomarkers of exposure. However, DNA adducts of various types are also produced endogenously in the course of normal metabolism. Since both endogenous physiological processes and exogenous exposure to xenobiotics can cause DNA adducts, the differentiation of the sources of DNA adducts can be highly informative for cancer risk assessment. This review summarizes a highly applicable methodology, termed stable isotope labeling and mass spectrometry (SILMS), that is superior to previous methods, as it not only provides absolute quantitation of DNA adducts but also differentiates the exogenous and endogenous origins of DNA adducts. SILMS uses stable isotope-labeled substances for exposure, followed by DNA adduct measurement with highly sensitive mass spectrometry. Herein, the utilities and advantage of SILMS have been demonstrated by the rich data sets generated over the last two decades in improving the risk assessment of chemicals with DNA adducts being induced by both endogenous and exogenous sources, such as formaldehyde, vinyl acetate, vinyl chloride, and ethylene oxide.
Topics: Animals; Carcinogens; DNA Adducts; Humans; Isotope Labeling; Mass Spectrometry
PubMed: 34910474
DOI: 10.1021/acs.chemrestox.1c00212 -
Chemical Research in Toxicology Feb 2020Genome integrity is constantly challenged by endogenous or exogenous genotoxic agents, which can give rise to various DNA adducts. After metabolic activation,...
Genome integrity is constantly challenged by endogenous or exogenous genotoxic agents, which can give rise to various DNA adducts. After metabolic activation, tobacco-specific nitrosamines '-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) can lead to pyridyloxobutylphosphotriesters (POB-PTEs) in DNA. Here, we synthesized oligodeoxyribonucleotides containing a site-specifically inserted - or -POB-PTE flanked by two thymidines, and we examined the impact that these lesions have on DNA replication in cells. We found that these two lesions are not strong impediments to DNA replication, and their replicative bypass is not modulated by genetic depletion of the three SOS-induced DNA polymerases or Ada protein. In addition, neither - nor -POB-PTEs was mutagenic in cells. Together, our study unveiled, for the first time, the influence of tobacco-specific nitrosamine-induced POB-PTE lesions on DNA replication .
Topics: DNA Adducts; DNA Replication; Escherichia coli; Molecular Structure; Organophosphonates; Pyridines
PubMed: 31916443
DOI: 10.1021/acs.chemrestox.9b00485 -
DNA Repair Oct 2020Topoisomerases play a pivotal role in ensuring DNA metabolisms during replication, transcription and chromosomal segregation. To manage DNA topology, topoisomerases... (Review)
Review
Topoisomerases play a pivotal role in ensuring DNA metabolisms during replication, transcription and chromosomal segregation. To manage DNA topology, topoisomerases generate break(s) in the DNA backbone by forming transient enzyme-DNA cleavage complexes (TOPcc) with phosphotyrosyl linkages between DNA ends and topoisomerase catalytic tyrosyl residues. Topoisomerases have been identified as the cellular targets of a variety of anti-cancer drugs (e.g. topotecan, irinotecan, etoposide and doxorubicin, and antibiotics (e.g. ciprofloxacin and levofloxacin). These drugs, as well as other exogenous and endogenous agents, convert the transient TOPcc into persistent TOPcc, which we refer to as topoisomerase DNA-protein crosslinks (TOP-DPC) that challenge genome integrity and lead to cell death if left unrepaired. Proteolysis of the bulky protein component of TOP-DPC (debulking) is a poorly understood repair process employed across eukaryotes. TOP-DPC proteolysis can be achieved either by the ubiquitin-proteasome pathway (UPP) or by non-proteasomal proteases, which are typified by the metalloprotease SPRTN/WSS1. Debulking of TOP-DPC exposes the phosphotyrosyl bonds, hence enables tyrosyl-DNA phosphodiesterases (TDP1 and TDP2) to access and cleave the bonds. In this review, we focus on current knowledge of the protease pathways for debulking TOP-DPC and highlighting recent advances in understanding the mechanisms regulating the proteolytic repair pathways. We also discuss the avenues that are being exploited to target the proteolytic repair pathways for improving the clinical outcome of topoisomerase inhibitors.
Topics: Animals; DNA; DNA Adducts; DNA Repair; DNA Topoisomerases; Eukaryota; Humans; Phosphoric Diester Hydrolases; Proteasome Endopeptidase Complex; Proteolysis; Topoisomerase Inhibitors
PubMed: 32674013
DOI: 10.1016/j.dnarep.2020.102926 -
Cellular and Molecular Life Sciences :... Aug 2016Interstrand crosslinks (ICLs) are a highly toxic form of DNA damage. ICLs can interfere with vital biological processes requiring separation of the two DNA strands, such... (Review)
Review
Interstrand crosslinks (ICLs) are a highly toxic form of DNA damage. ICLs can interfere with vital biological processes requiring separation of the two DNA strands, such as replication and transcription. If ICLs are left unrepaired, it can lead to mutations, chromosome breakage and mitotic catastrophe. The Fanconi anemia (FA) pathway can repair this type of DNA lesion, ensuring genomic stability. In this review, we will provide an overview of the cellular response to ICLs. First, we will discuss the origin of ICLs, comparing various endogenous and exogenous sources. Second, we will describe FA proteins as well as FA-related proteins involved in ICL repair, and the post-translational modifications that regulate these proteins. Finally, we will review the process of how ICLs are repaired by both replication-dependent and replication-independent mechanisms.
Topics: Animals; Cross-Linking Reagents; DNA; DNA Adducts; DNA Damage; DNA Repair; DNA Replication; Fanconi Anemia Complementation Group Proteins; Genomic Instability; Humans; Intercalating Agents; Models, Molecular; Protein Processing, Post-Translational; Signal Transduction
PubMed: 27094386
DOI: 10.1007/s00018-016-2218-x -
Chemical Research in Toxicology Aug 2020The human intestine is host to a vast microbial community: the gut microbiome (GM). The GM has been considered as a key modulator of human health in the past decade. In...
The human intestine is host to a vast microbial community: the gut microbiome (GM). The GM has been considered as a key modulator of human health in the past decade. In particular, several studies have supported that altered GM is associated with cancer, such as colorectal cancer, adenocarcinoma, and pancreatic cancer. The formation of a DNA adduct is one of the key events in carcinogenesis, and whether GM can influence DNA adducts has yet to be examined. This study analyzed 10 DNA adducts (N-Me-dG, N-Me-dA, N-Et-dG, OH-Me-dG, OH-Me-dA, N-EtD-dG, O-Me-dG, 1,N-ε-dG, 8-oxo-dG, and 5-Cl-dC), attributed to various endogenous processes and physiological stressors, using highly sensitive LC-MS/MS in germ-free (GF) and conventionally raised (CONV-R) mice. Our results showed that significant differences in specific DNA adducts appeared in liver, colon, and small intestine samples between GF and CONV-R mice. The differences in adduct levels may indicate that GM can locally or systemically regulate endogenous processes including neutrophil bactericidal activity (represented by 5-Cl-dC), lipid peroxidation (1,N-ε-dG), oxidative stress generation (8-oxo-dG), and endogenous aldehyde metabolism (OH-Me-dA). Further studies are warranted to elucidate how the GM influences endogenous process, DNA damage, and the risks of developing cancer.
Topics: Animals; Carcinogenesis; Carcinogens; DNA Adducts; DNA Damage; Female; Gastrointestinal Microbiome; Mice; Mice, Inbred C57BL; Molecular Structure
PubMed: 32677427
DOI: 10.1021/acs.chemrestox.0c00142 -
Chemical Society Reviews Nov 2015Exogenous and endogenous sources of chemical species can react, directly or after metabolic activation, with DNA to yield DNA adducts. If not repaired, DNA adducts may... (Review)
Review
Exogenous and endogenous sources of chemical species can react, directly or after metabolic activation, with DNA to yield DNA adducts. If not repaired, DNA adducts may compromise cellular functions by blocking DNA replication and/or inducing mutations. Unambiguous identification of the structures and accurate measurements of the levels of DNA adducts in cellular and tissue DNA constitute the first and important step towards understanding the biological consequences of these adducts. The advances in mass spectrometry (MS) instrumentation in the past 2-3 decades have rendered MS an important tool for structure elucidation, quantification, and revelation of the biological consequences of DNA adducts. In this review, we summarized the development of MS techniques on these fronts for DNA adduct analysis. We placed our emphasis of discussion on sample preparation, the combination of MS with gas chromatography- or liquid chromatography (LC)-based separation techniques for the quantitative measurement of DNA adducts, and the use of LC-MS along with molecular biology tools for understanding the human health consequences of DNA adducts. The applications of mass spectrometry-based DNA adduct analysis for predicting the therapeutic outcome of anti-cancer agents, for monitoring the human exposure to endogenous and environmental genotoxic agents, and for DNA repair studies were also discussed.
Topics: Chromatography, Liquid; DNA Adducts; Spectrometry, Mass, Electrospray Ionization
PubMed: 26204249
DOI: 10.1039/c5cs00316d