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Nature Communications Nov 2023As observed in cancers, individual mutagens and defects in DNA repair create distinctive mutational signatures that combine to form context-specific spectra within...
As observed in cancers, individual mutagens and defects in DNA repair create distinctive mutational signatures that combine to form context-specific spectra within cells. We reasoned that similar processes must occur in bacterial lineages, potentially allowing decomposition analysis to detect both disruption of DNA repair processes and exposure to niche-specific mutagens. Here we reconstruct mutational spectra for 84 clades from 31 diverse bacterial species and find distinct mutational patterns. We extract signatures driven by specific DNA repair defects using hypermutator lineages, and further deconvolute the spectra into multiple signatures operating within different clades. We show that these signatures are explained by both bacterial phylogeny and replication niche. By comparing mutational spectra of clades from different environmental and biological locations, we identify niche-associated mutational signatures, and then employ these signatures to infer the predominant replication niches for several clades where this was previously obscure. Our results show that mutational spectra may be associated with sites of bacterial replication when mutagen exposures differ, and can be used in these cases to infer transmission routes for established and emergent human bacterial pathogens.
Topics: Humans; Mutation; Neoplasms; DNA Repair; Mutagens; DNA Mutational Analysis
PubMed: 37925514
DOI: 10.1038/s41467-023-42916-w -
Arhiv Za Higijenu Rada I Toksikologiju Mar 2020Despite its evidenced beneficial herbicidal, antibacterial, antiviral, antifungal, and antioxidant effects, the application of juglone (5-hydroxy-1,4,-naphthoquinone) is... (Comparative Study)
Comparative Study
Despite its evidenced beneficial herbicidal, antibacterial, antiviral, antifungal, and antioxidant effects, the application of juglone (5-hydroxy-1,4,-naphthoquinone) is limited due to its low water solubility and allelopathic and toxic effects. In recent years, research has aimed to overcome these limitations by increasing its solubility and controlling its release through nanoparticular systems. This is the first study to have synthesised and characterised juglone-loaded polymeric nanoparticles and compared them with free juglone for cytotoxicity in mouse (L929 fibroblasts) and alfalfa cells and for mutagenic potential in Salmonella typhimurium TA98/100. Mouse and plant cells treated with free and nano-encapsulated juglone showed a decrease in cell viability in a dose and time-dependent manner, but this effect was significantly lower with the nano-encapsulated form at lower doses. In the TA98 strain with S9, nano-encapsulated juglone did not exhibit mutagenic effects, unlike the free form. Since all results show that juglone encapsulation with polymeric nanoparticles reduced the toxic and mutagenic effects, it has a promising potential to be applied in medicine, food safety, and agriculture.
Topics: Animals; Cell Survival; Cytotoxins; Fibroblasts; Medicago sativa; Mice; Mutagens; Naphthoquinones; Solubility
PubMed: 32597139
DOI: 10.2478/aiht-2020-71-3344 -
Cold Spring Harbor Perspectives in... Mar 2021Observations of the incidence of tumors among chimney sweeps in the eighteenth century and later experiments with coal tars provided early evidence that carcinogens in... (Review)
Review
Observations of the incidence of tumors among chimney sweeps in the eighteenth century and later experiments with coal tars provided early evidence that carcinogens in the environment can promote cancer. Subsequent studies of individuals exposed to radiation, work on fly genetics, and the discovery that DNA was the genetic material led to the idea that these carcinogens act by inducing mutations in DNA that change the behavior of cells and ultimately cause cancer. In this excerpt from his forthcoming book, Joe Lipsick looks back at how the concepts of mutagenesis and carcinogenesis emerged, how these converged with development of the Ames test, and how biochemistry and crystallography ultimately revealed the underlying molecular basis.
Topics: Biomedical Research; Carcinogens; History, 18th Century; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Mutagens; Mutation; Neoplasms; Occupational Diseases
PubMed: 33649023
DOI: 10.1101/cshperspect.a035857 -
Archives of Toxicology Jun 2020The risk assessment of chemical carcinogens is one major task in toxicology. Even though exposure has been mitigated effectively during the last decades, low levels of... (Review)
Review
The risk assessment of chemical carcinogens is one major task in toxicology. Even though exposure has been mitigated effectively during the last decades, low levels of carcinogenic substances in food and at the workplace are still present and often not completely avoidable. The distinction between genotoxic and non-genotoxic carcinogens has traditionally been regarded as particularly relevant for risk assessment, with the assumption of the existence of no-effect concentrations (threshold levels) in case of the latter group. In contrast, genotoxic carcinogens, their metabolic precursors and DNA reactive metabolites are considered to represent risk factors at all concentrations since even one or a few DNA lesions may in principle result in mutations and, thus, increase tumour risk. Within the current document, an updated risk evaluation for genotoxic carcinogens is proposed, based on mechanistic knowledge regarding the substance (group) under investigation, and taking into account recent improvements in analytical techniques used to quantify DNA lesions and mutations as well as "omics" approaches. Furthermore, wherever possible and appropriate, special attention is given to the integration of background levels of the same or comparable DNA lesions. Within part A, fundamental considerations highlight the terms hazard and risk with respect to DNA reactivity of genotoxic agents, as compared to non-genotoxic agents. Also, current methodologies used in genetic toxicology as well as in dosimetry of exposure are described. Special focus is given on the elucidation of modes of action (MOA) and on the relation between DNA damage and cancer risk. Part B addresses specific examples of genotoxic carcinogens, including those humans are exposed to exogenously and endogenously, such as formaldehyde, acetaldehyde and the corresponding alcohols as well as some alkylating agents, ethylene oxide, and acrylamide, but also examples resulting from exogenous sources like aflatoxin B, allylalkoxybenzenes, 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeIQx), benzo[a]pyrene and pyrrolizidine alkaloids. Additionally, special attention is given to some carcinogenic metal compounds, which are considered indirect genotoxins, by accelerating mutagenicity via interactions with the cellular response to DNA damage even at low exposure conditions. Part C finally encompasses conclusions and perspectives, suggesting a refined strategy for the assessment of the carcinogenic risk associated with an exposure to genotoxic compounds and addressing research needs.
Topics: Animals; Carcinogenicity Tests; Carcinogens; DNA Damage; Humans; Mutagenicity Tests; Mutagens; Risk Assessment; Toxicogenetics
PubMed: 32542409
DOI: 10.1007/s00204-020-02733-2 -
Environmental Science and Pollution... Sep 2022Despite the association between tobacco use and the harmful effects on general health as well as male fertility parameters, smoking remains globally prevalent. The main... (Review)
Review
Despite the association between tobacco use and the harmful effects on general health as well as male fertility parameters, smoking remains globally prevalent. The main content of tobacco smoke is nicotine and its metabolite cotinine. These compounds can pass the blood-testis barrier, which subsequently causes harm of diverse degree to the germ cells. Although controversial, smoking has been shown to cause not only a decrease in sperm motility, sperm concentration, and an increase in abnormal sperm morphology, but also genetic and epigenetic aberrations in spermatozoa. Both animal and human studies have highlighted the occurrence of sperm DNA-strand breaks (fragmentation), genome instability, genetic mutations, and the presence of aneuploids in the germline of animals and men exposed to tobacco smoke. The question to be asked at this point is, if smoking has the potential to cause all these genetic aberrations, what is the extent of damage? Hence, this review aimed to provide evidence that smoking has a mutagenic effect on sperm and how this subsequently affects male fertility. Additionally, the role of tobacco smoke as an aneugen will be explored. We furthermore aim to incorporate the epidemiological aspects of the aforementioned and provide a holistic approach to the topic.
Topics: Animals; Fertility; Humans; Male; Mutagens; Seeds; Smoke; Sperm Motility; Spermatozoa; Nicotiana; Tobacco Smoke Pollution
PubMed: 34536221
DOI: 10.1007/s11356-021-16331-x -
Genes Feb 2022The identification of mutants through forward genetic screens is the backbone of genetics research, yet many mutants identified through these screens have yet to be...
The identification of mutants through forward genetic screens is the backbone of genetics research, yet many mutants identified through these screens have yet to be mapped to the genome. This is especially true of mutants that have been identified as mutagen-sensitive (), but have not yet been mapped to their associated molecular locus. Our study addressed the need for additional gene identification by determining the locus and exploring the function of the -linked mutagen-sensitive gene using three available mutant alleles: , , and . After first confirming that all three alleles were sensitive to methyl methanesulfonate (MMS) using complementation analysis, we used deletion mapping to narrow the candidate genes for Through DNA sequencing, we were able to determine that is the uncharacterized gene which encodes the ortholog of the highly conserved DNA2 protein that is important for DNA replication and repair. We further used the sequence and structure of DNA2 to predict the impact of the allele mutations on the final gene product. Together, these results provide a tool for researchers to further investigate the role of DNA2 in DNA repair processes in
Topics: Animals; DNA Repair; Drosophila; Drosophila melanogaster; Methyl Methanesulfonate; Mutagens
PubMed: 35205357
DOI: 10.3390/genes13020312 -
International Journal of Environmental... Jan 2020There are presently more than 18 known aflatoxins most of which have been insufficiently studied for their incidence, health-risk, and mechanisms of toxicity to allow... (Review)
Review
There are presently more than 18 known aflatoxins most of which have been insufficiently studied for their incidence, health-risk, and mechanisms of toxicity to allow effective intervention and control means that would significantly and sustainably reduce their incidence and adverse effects on health and economy. Among these, aflatoxin B1 (AFB1) has been by far the most studied; yet, many aspects of the range and mechanisms of the diseases it causes remain to be elucidated. Its mutagenicity, tumorigenicity, and carcinogenicity-which are the best known-still suffer from limitations regarding the relative contribution of the oxidative stress and the reactive epoxide derivative (Aflatoxin-exo 8,9-epoxide) in the induction of the diseases, as well as its metabolic and synthesis pathways. Additionally, despite the well-established additive effects for carcinogenicity between AFB1 and other risk factors, e.g., hepatitis viruses B and C, and the hepatotoxic algal microcystins, the mechanisms of this synergy remain unclear. This study reviews the most recent advances in the field of the mechanisms of toxicity of aflatoxins and the adverse health effects that they cause in humans and animals.
Topics: Aflatoxins; Animals; Chronic Disease; Humans; Immune System; Mutagens; Neoplasms; Teratogens
PubMed: 31936320
DOI: 10.3390/ijerph17020423 -
Theranostics 2020A cluster of patients poisoned by herbal medicine in the 1990s revealed that aristolochic acid (AA) causes kidney failure and upper tract urothelial carcinoma (UTUC)....
A cluster of patients poisoned by herbal medicine in the 1990s revealed that aristolochic acid (AA) causes kidney failure and upper tract urothelial carcinoma (UTUC). Recent research demonstrated that this was not an isolated incident; on the contrary, AA exposure is widespread in East Asia. This editorial highlights research by Lu and colleagues that investigates clinical characteristics of AA and non-AA UTUCs from 90 patients in Beijing based on the AA mutational signature. The study also detected AA mutations in non-tumor tissue of AA exposed patients and showed that AA mutations can be detected in urine, which might form the basis for non-invasive tests for AA exposure.
Topics: Aristolochic Acids; Humans; Mutagens; Mutation; Neoplasm Proteins; Urinary Bladder Neoplasms; Urothelium
PubMed: 32373232
DOI: 10.7150/thno.46489 -
Nature Communications May 2023UV exposure induces a mutation signature of C > T substitutions at dipyrimidines in skin cancers. We recently identified additional UV-induced AC > TT and...
UV exposure induces a mutation signature of C > T substitutions at dipyrimidines in skin cancers. We recently identified additional UV-induced AC > TT and A > T substitutions that could respectively cause BRAF V600K and V600E oncogenic mutations. The mutagenic bypass mechanism past these atypical lesions, however, is unknown. Here, we whole genome sequenced UV-irradiated yeast and used reversion reporters to delineate the roles of replicative and translesion DNA polymerases in mutagenic bypass of UV-lesions. Our data indicates that yeast DNA polymerase eta (pol η) has varied impact on UV-induced mutations: protecting against C > T substitutions, promoting T > C and AC > TT substitutions, and not impacting A > T substitutions. Surprisingly, deletion rad30Δ increased novel UV-induced C > A substitutions at CA dinucleotides. In contrast, DNA polymerases zeta (pol ζ) and epsilon (pol ε) participated in AC > TT and A > T mutations. These results uncover lesion-specific accurate and mutagenic bypass of UV lesions, which likely contribute to key driver mutations in melanoma.
Topics: DNA Damage; Mutagens; Saccharomyces cerevisiae; Ultraviolet Rays; DNA-Directed DNA Polymerase; DNA Replication
PubMed: 37142570
DOI: 10.1038/s41467-023-38255-5 -
Nature Chemical Biology Feb 2023The human gut bacterial genotoxin colibactin is a possible key driver of colorectal cancer (CRC) development. Understanding colibactin's biological effects remains...
The human gut bacterial genotoxin colibactin is a possible key driver of colorectal cancer (CRC) development. Understanding colibactin's biological effects remains difficult owing to the instability of the proposed active species and the complexity of the gut microbiota. Here, we report small molecule boronic acid inhibitors of colibactin biosynthesis. Designed to mimic the biosynthetic precursor precolibactin, these compounds potently inhibit the colibactin-activating peptidase ClbP. Using biochemical assays and crystallography, we show that they engage the ClbP binding pocket, forming a covalent bond with the catalytic serine. These inhibitors reproduce the phenotypes observed in a clbP deletion mutant and block the genotoxic effects of colibactin on eukaryotic cells. The availability of ClbP inhibitors will allow precise, temporal control over colibactin production, enabling further study of its contributions to CRC. Finally, application of our inhibitors to related peptidase-encoding pathways highlights the power of chemical tools to probe natural product biosynthesis.
Topics: Humans; Mutagens; Escherichia coli; Gastrointestinal Microbiome; Polyketides; Peptide Hydrolases
PubMed: 36253549
DOI: 10.1038/s41589-022-01147-8