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The biosynthetic machinery for the production of colibactin is encoded by 19 genes (clbA - S) within the pks pathogenicity island harboured by many E. coli of the B2-phylogroup. Colibactin is a potent genotoxic metabolite which causes DNA-damage and which has potential roles in microbial competition and fitness of pks+ bacteria. Colibactin has also been strongly implicated in the development of colorectal cancer. Given the genotoxicity of colibactin and the metabolic cost of its synthesis, the regulatory system governing the clb cluster is accordingly highly complex, and many of the mechanisms remain to be elucidated. In this review we summarise the current understanding of regulation of colibactin biosynthesis by internal molecular components and how these factors are modulated by signals from the external environment.
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Proteínas de Escherichia coli , Policetídeos , Escherichia coli/genética , Escherichia coli/metabolismo , Peptídeos/genética , Peptídeos/metabolismo , Proteínas de Escherichia coli/metabolismo , Policetídeos/metabolismoRESUMO
Micronuclei (MN) are induced by various genotoxic stressors and amass nuclear- and cytoplasmic-resident proteins, priming the cell for MN-driven signaling cascades. Here, we measured the proteome of micronuclear, cytoplasmic, and nuclear fractions from human cells exposed to a panel of six genotoxins, comprehensively profiling their MN protein landscape. We find that MN assemble a proteome distinct from both surrounding cytoplasm and parental nuclei, depleted of spliceosome and DNA damage repair components while enriched for a subset of the replisome. We show that the depletion of splicing machinery within transcriptionally active MN contributes to intra-MN DNA damage, a known precursor to chromothripsis. The presence of transcription machinery in MN is stress-dependent, causing a contextual induction of MN DNA damage through spliceosome deficiency. This dataset represents a unique resource detailing the global proteome of MN, guiding mechanistic studies of MN generation and MN-associated outcomes of genotoxic stress.
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Cromotripsia , Proteoma , Humanos , Proteoma/genética , Proteoma/metabolismo , Proteômica , Núcleo Celular/genética , Núcleo Celular/metabolismo , Dano ao DNA/genéticaRESUMO
Drosophila melanogaster is one of the crucial in vivo models in terms of analyzing the toxicity of various unknown chemicals. Every part of the fly serves as a model in metabolic and therapeutic approaches. Genotoxic and teratogenic compounds are exposed to Drosophila through the oral route. Further, the toxicity of genotoxic compounds is analyzed in Drosophila's gut, hemolymph, and phenotype. The toxicity of teratogen compounds is also analyzed using a Drosophila embryo. The current chapter summarizes several techniques that are used to detect the genotoxicity and teratogenicity of any unknown compound in this model.
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Teratogênese , Teratogênicos , Animais , Teratogênicos/toxicidade , Drosophila melanogaster/genética , Drosophila , Dano ao DNARESUMO
Disinfection by-products (DBPs) are a concern due to their presence in chlorinated wastewater, sewage treatment plant discharge, and surface water, and their potential for environmental toxicity. Despite some attention to their ecotoxicity, little is known about the phytotoxicity of DBPs. This study aimed to evaluate the individual and combined phytotoxicity of four trihalomethanes (THMs: trichloromethane (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM), and tribromomethane (TBM) and their mixture (THM4)), and trichloroacetic acid (TCAA) using genotoxic and cytotoxic assays. The analysis included seed germination tests using Vigna radiata and root growth tests, mitosis studies, oxidative stress response, chromosomal aberrations (CA), and DNA laddering using Allium cepa. The results showed a progressive increase in root growth inhibition for both plant species as the concentration of DBPs increased. High concentrations of mixtures of four THMs resulted in significant (p < 0.05) antagonistic interactions. The effective concentration (EC50) value for V. radiata was 5655, 3145, 2690, 1465, 3570, and 725 mg/L for TCM, BDCM, DBCM, TBM, THM4, and TCAA, respectively. For A. cepa, the EC50 for the same contaminants was 700, 400, 350, 250, 450, and 105 mg/L, respectively. DBP cytotoxicity was observed through CAs, including C-metaphase, unseparated anaphase, lagging chromosome, sticky metaphase, and bridging. Mitotic depression (MD) increased with dose, reaching up to 54.4% for TCAA (50-500 mg/L). The electrophoresis assay showed DNA fragmentation and shearing, suggesting genotoxicity for some DBPs. The order of phytotoxicity for the tested DBPs was TCAA > TBM > DBCM > BDCM > THM4 > TCM. These findings underscore the need for further research on the phytotoxicity of DBPs, especially given their common use in agricultural practices such as irrigation and the use of sludge as manure.
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Vigna , Poluentes Químicos da Água , Ácido Tricloroacético/toxicidade , Cebolas , Trialometanos/toxicidade , Desinfecção/métodos , Clorofórmio , Poluentes Químicos da Água/toxicidadeRESUMO
Introduction: Pathogenic strains of Escherichia coli have been clearly identified as the causative agents of extraintestinal and diarrheal infections; however, the etiopathogenic role of E. coli in other conditions, including colorectal cancer, remains unclear. Methods: This study aimed to characterize mucosal E. coli isolates (n = 246) from 61 neoplasia patients and 20 healthy controls for the presence of 35 genetic determinants encoding known virulence factors. Results: Virulence determinants encoding invasin (ibeA), siderophore receptor (iroN), S-fimbriae (sfa), and genotoxin (usp) were more prevalent among E. coli isolated from patients with neoplasia compared to the control group (p < 0.05). In addition, the prevalence of these virulence determinants was increased in more advanced neoplasia stages (p adj < 0.0125). Compared to patients with advanced colorectal adenoma and carcinoma, the ibeA gene was rarely found in the control group and among patients with non-advanced adenoma (p < 0.05), indicating its potential as the advanced-neoplasia biomarker. Patients with neoplasia frequently had E. coli strains with at least one of the abovementioned virulence factors, whereby specific combinations of these virulence factors were found. Discussion: These findings suggest that E. coli strains isolated from patients with colorectal neoplasia possess several virulence factors, which could contribute to the development of neoplastic processes in the large intestine.
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Two herbal plants, Akebia quinata D. leaf/fruit and Clitoria ternatea L. flower, well-known in traditional medicine systems, were investigated using a non-target effect-directed profiling. High-performance thin-layer chromatography (HPTLC) was combined with 11 different effect-directed assays, including two multiplex bioassays, for assessing their bioactivity. Individual active zones were heart-cut eluted for separation via an orthogonal high-performance liquid chromatography column to heated electrospray ionization high-resolution mass spectrometry (HPLC-HESI-HRMS) for tentative assignment of molecular formulas according to literature data. The obtained effect-directed profiles provided information on 2,2-diphenyl-1-picrylhydrazyl scavenging, antibacterial (against Bacillus subtilis and Aliivibrio fischeri), enzyme inhibition (tyrosinase, α-amylase, ß-glucuronidase, butyrylcholinesterase, and acetylcholinesterase), endocrine (agonists and antagonists), and genotoxic (SOS-Umu-C) activities. The main bioactive compound zones in A. quinata leaf were tentatively assigned to be syringin, vanilloloside, salidroside, α-hederin, cuneataside E, botulin, and oleanolic acid, while salidroside and quinatic acids were tentatively identified in the fruit. Taraxerol, kaempherol-3-rutinoside, kaempferol-3-glucoside, quercetin-3-rutinoside, and octadecenoic acid were tentatively found in the C. ternatea flower. This straightforward hyphenated technique made it possible to correlate the biological properties of the herbs with possible compounds. The meaningful bioactivity profiles contribute to a better understanding of the effects and to more efficient food control and food safety.
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Clitoria , Acetilcolinesterase/química , Cromatografia em Camada Fina/métodos , Butirilcolinesterase , Extratos Vegetais/química , Espectrometria de Massas por Ionização por Electrospray , BioensaioRESUMO
The identity and role of environmental factors in the etiology of sporadic amyotrophic lateral sclerosis (sALS) is poorly understood outside of three former high-incidence foci of Western Pacific ALS and a hotspot of sALS in the French Alps. In both instances, there is a strong association with exposure to DNA-damaging (genotoxic) chemicals years or decades prior to clinical onset of motor neuron disease. In light of this recent understanding, we discuss published geographic clusters of ALS, conjugal cases, single-affected twins, and young-onset cases in relation to their demographic, geographic and environmental associations but also whether, in theory, there was the possibility of exposure to genotoxic chemicals of natural or synthetic origin. Special opportunities to test for such exposures in sALS exist in southeast France, northwest Italy, Finland, the U.S. East North Central States, and in the U.S. Air Force and Space Force. Given the degree and timing of exposure to an environmental trigger of ALS may be related to the age at which the disease is expressed, research should focus on the lifetime exposome (from conception to clinical onset) of young sALS cases. Multidisciplinary research of this type may lead to the identification of ALS causation, mechanism, and primary prevention, as well as to early detection of impending ALS and pre-clinical treatment to slow development of this fatal neurological disease.
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The DNA-alkylating metabolite tilimycin is a microbial genotoxin. Intestinal accumulation of tilimycin in individuals carrying til+ Klebsiella spp. causes apoptotic erosion of the epithelium and colitis. Renewal of the intestinal lining and response to injury requires the activities of stem cells located at the base of intestinal crypts. This study interrogates the consequences of tilimycin-induced DNA damage to cycling stem cells. We charted the spatial distribution and luminal quantities of til metabolites in Klebsiella-colonized mice in the context of a complex microbial community. Loss of marker gene G6pd function indicates genetic aberrations in colorectal stem cells that became stabilized in monoclonal mutant crypts. Mice colonized with tilimycin-producing Klebsiella displayed both higher frequencies of somatic mutation and more mutations per affected individual than animals carrying a non-producing mutant. Our findings imply that genotoxic til+ Klebsiella may drive somatic genetic change in the colon and increase disease susceptibility in human hosts.
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Microbiota , Mutagênicos , Humanos , Camundongos , Animais , Mutagênicos/metabolismo , Colo/metabolismo , Mutação/genética , Células-Tronco , Mucosa IntestinalRESUMO
The etiology of colorectal cancer (CRC) is influenced by bacterial communities that colonize the gastrointestinal tract. These microorganisms derive essential nutrients from indigestible dietary or host-derived compounds and activate molecular signaling pathways necessary for normal tissue and immune function. Associative and mechanistic studies have identified bacterial species whose presence may increase CRC risk, including notable examples such as Fusobacterium nucleatum, Enterotoxigenic Bacteroides fragilis, and pks+ E. coli. In recent years this work has expanded in scope to include aspects of host mutational status, intra-tumoral microbial heterogeneity, transient infection, and the cumulative influence of multiple carcinogenic bacteria after sequential or co-colonization. In this review, we will provide an updated overview of how host-bacteria interactions influence CRC development, how this knowledge may be utilized to diagnose or prevent CRC, and how the gut microbiome influences CRC treatment efficacy.
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Infecções Bacterianas , Neoplasias Colorretais , Microbioma Gastrointestinal , Humanos , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/terapia , Escherichia coli , Fusobacterium nucleatumRESUMO
Some Escherichia coli strains harbour the pks island, a 54 kb genomic island encoding the biosynthesis genes for a genotoxic compound named colibactin. In eukaryotic cells, colibactin can induce DNA damage, cell cycle arrest and chromosomal instability. Production of colibactin has been implicated in the development of colorectal cancer (CRC). In this study, we demonstrate the inhibitory effect of D-Serine on the expression of the pks island in both prototypic and clinically-associated colibactin-producing strains and determine the implications for cytopathic effects on host cells. We also tested a comprehensive panel of proteinogenic L-amino acids and corresponding D-enantiomers for their ability to modulate clbB transcription. Whilst several D-amino acids exhibited the ability to inhibit expression of clbB, D-Serine exerted the strongest repressing activity (>3.8-fold) and thus, we focussed additional experiments on D-Serine. To investigate the cellular effect, we investigated if repression of colibactin by D-Serine could reduce the cytopathic responses normally observed during infection of HeLa cells with pks + strains. Levels of γ-H2AX (a marker of DNA double strand breaks) were reduced 2.75-fold in cells infected with D-Serine treatment. Moreover, exposure of pks + E. coli to D-Serine during infection caused a reduction in cellular senescence that was observable at 72 h post infection. The recent finding of an association between pks-carrying commensal E. coli and CRC, highlights the necessity for the development of colibactin targeting therapeutics. Here we show that D-Serine can reduce expression of colibactin, and inhibit downstream cellular cytopathy, illuminating its potential to prevent colibactin-associated disease.
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The arginine dependency of cancer cells creates metabolic vulnerability. In this study, we examine the impact of arginine availability on DNA replication and genotoxicity resistance. Using DNA combing assays, we find that limiting extracellular arginine results in the arrest of cancer cells at S phase and a slowing or stalling of DNA replication. The translation of new histone H4 is arginine dependent and influences DNA replication. Increased proliferating cell nuclear antigen (PCNA) occupancy and helicase-like transcription factor (HLTF)-catalyzed PCNA K63-linked polyubiquitination protect arginine-starved cells from DNA damage. Arginine-deprived cancer cells display tolerance to genotoxicity in a PCNA K63-linked polyubiquitination-dependent manner. Our findings highlight the crucial role of extracellular arginine in nutrient-regulated DNA replication and provide potential avenues for the development of cancer treatments.
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Dano ao DNA , Histonas , Antígeno Nuclear de Célula em Proliferação/metabolismo , Histonas/metabolismo , Ubiquitinação , Replicação do DNARESUMO
BACKGROUND: New evidence suggests that bacteria-produced DNA toxins may have a role in the development or progression of prostate cancer. To determine the prevalence of these genes in a noninfection (i.e., colonized) state, we screened urine specimens in men before undergoing a biopsy for prostate cancer detection. METHODS: We developed a multiplex polymerase chain reaction using three of the most described bacterial genotoxin gene primers: Colibactin (polyketone synthase [pks] gene island: clbN and clbB), cytotoxic necrotizing factor (cnf1) toxin, and cytolethal distending toxin B (cdtB) represented gene islands. After calibration on Escherichia coli samples of known genotypes, we used a training and validation cohort. We performed multiplex testing on a training cohort of previously collected urine from 45 men undergoing prostate biopsy. For the validation cohort, we utilized baseline urine samples from a previous randomized clinical trial (n = 263) with known prostate cancer outcomes. RESULTS: The prevalence of four common bacterial genotoxin genes detected in the urine before prostate biopsy for prostate cancer is 8% (25/311). The prevalence of pks island (clbN and clbB), cnf1, and cdt toxin genes are 6.1%, 2.4%, and 1.7%, respectively. We found no association between urinary genotoxins and prostate cancer (p = 0.83). We did identify a higher proportion of low-grade cancer (92% vs. 44%) in those men positive for urinary genotoxin and higher-grade cancer in those genotoxin negative (8% vs. 56%, p = 0.001). CONCLUSIONS: The prevalence of urinary genotoxins is low and does not correspond to a prostate cancer diagnosis. The urine was taken at one point in time and does not rule out the possibility of previous exposure.
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Escherichia coli , Neoplasias da Próstata , Masculino , Humanos , Prevalência , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Biópsia , Dano ao DNA , MutagênicosRESUMO
Planar chromatography has recently been combined with six different effect-directed assays for three golden root (Rhodiola rosea L.) samples. However, the profiles obtained showed an intense tailing, making zone differentiation impossible. The profiling was therefore improved to allow for the detection of individual bioactive compounds, and the range of samples was extended to 15 commercial golden root products. Further effect-directed assays were studied providing information on 15 different effect mechanisms, i.e., (1) tyrosinase, (2) acetylcholinesterase, (3) butyrylcholinesterase, (4) ß-glucuronidase, and (5) α-amylase inhibition, as well as endocrine activity via the triplex planar yeast antagonist-verified (6-8) estrogen or (9-11) androgen screen, (12) genotoxicity via the planar SOS-Umu-C bioassay, antimicrobial activity against (13) Gram-negative Aliivibrio fischeri and (14) Gram-positive Bacillus subtilis bacteria, and (15) antioxidative activity (DPPH⢠radical scavengers). Most of the golden root profiles obtained were characteristic, but some samples differed substantially. The United States Pharmacopeia reference product showed medium activity in most of the assays. The six most active compound zones were further characterized using high-resolution mass spectrometry, and the mass signals obtained were tentatively assigned to molecular formulae. In addition to confirming the known activities, this study is the first to report that golden root constituents inhibit butyrylcholinesterase (rosin was tentatively assigned), ß-glucuronidase (rosavin, rosarin, rosiridin, viridoside, and salidroside were tentatively assigned), and α-amylase (stearic acid and palmitic acid were tentatively assigned) and that they are genotoxic (hydroquinone was tentatively assigned) and are both agonistic and antagonistic endocrine active.
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Acetilcolinesterase , Butirilcolinesterase , Butirilcolinesterase/farmacologia , Acetilcolinesterase/química , Extratos Vegetais/química , Cromatografia em Camada Fina/métodos , Espectrometria de Massas , Bacillus subtilis , Bioensaio , GlucuronidaseRESUMO
Emerging evidence indicates bacterial infections contribute to the formation of cancers. Bacterial genotoxins are effectors that cause DNA damage by introducing single- and double-strand DNA breaks in the host cells. The first bacterial genotoxin cytolethal distending toxin (CDT) was a protein identified in 1987 in a pathogenic strain in Escherichia coli (E. coli) isolated from a young patient. The peptide-polyketide genotoxin colibactin is produced by the phylogenetic group B2 of E. coli. Recently, a protein produced by attaching/effacing (A/E) pathogens, including enteropathogenic and enterohemorrhagic E. coli (EPEC and EHEC) and their murine equivalent Citrobacter rodentium (CR), has been reported as a novel protein genotoxin, being injected via the type III secretion system (T3SS) into host cells and harboring direct DNA digestion activity with a catalytic histidine-aspartic acid dyad. These E. coli-produced genotoxins impair host DNA, which results in senescence or apoptosis of the target cells if the damage is beyond repair. Conversely, host cells can survive and proliferate if the genotoxin-induced DNA damage is not severe enough to kill them. The surviving cells may accumulate genomic instability and acquire malignant traits. This review presents the cellular responses of infection with the genotoxins-producing E. coli and discusses the current knowledge of the tumorigenic potential of these toxins.
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Introduction: Typhoid toxin-expressing Salmonella enterica causes DNA damage in the intestinal mucosa in vivo, activating the DNA damage response (DDR) in the absence of inflammation. To understand whether the tissue microenvironment constrains the infection outcome, we compared the immune response and DDR patterns in the colon and liver of mice infected with a genotoxigenic strain or its isogenic control strain. Methods: In situ spatial transcriptomic and immunofluorescence have been used to assess DNA damage makers, activation of the DDR, innate immunity markers in a multiparametric analysis. Result: The presence of the typhoid toxin protected from colonic bacteria-induced inflammation, despite nuclear localization of p53, enhanced co-expression of type-I interferons (IfnbI) and the inflammasome sensor Aim2, both classic features of DNA-break-induced DDR activation. These effects were not observed in the livers of either infected group. Instead, in this tissue, the inflammatory response and DDR were associated with high oxidative stress-induced DNA damage. Conclusions: Our work highlights the relevance of the tissue microenvironment in enabling the typhoid toxin to suppress the host inflammatory response in vivo.
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Salmonella enterica , Febre Tifoide , Camundongos , Animais , Salmonella enterica/genética , Mutagênicos , Dano ao DNA , Inflamação , Reparo do DNARESUMO
Bacterial genotoxins are peptide or protein virulence factors produced by several pathogens, which make single-strand breaks (SSBs) and/or double-strand DNA breaks (DSBs) in the target host cells. If host DNA inflictions are not resolved on time, host cell apoptosis, cell senescence, and/or even bacterial pathogen-related cancer may occur. Two multi-protein AB toxins, cytolethal distending toxin (CDT) produced by over 30 bacterial pathogens and typhoid toxin from Salmonella Typhi, as well as small polyketide-peptides named colibactin that causes the DNA interstrand cross-linking and subsequent DSBs is the most well-characterized bacterial genotoxins. Using these three examples, this review discusses the mechanisms by which these toxins deliver themselves into the nucleus of the target host cells and exert their genotoxic functions at the structural and functional levels.
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Bactérias , Mutagênicos , Bactérias/metabolismo , Quebras de DNA de Cadeia Dupla , Dano ao DNA , Mutagênicos/metabolismo , Mutagênicos/toxicidade , Fatores de Virulência/genéticaRESUMO
The structure and mode of action of colibactin with its potential involvement in cancer have been extensively studied but little is known about the intrinsic function of the biosynthetic gene cluster, coding for colibactin, as a bacterial genotoxin. Paradoxically, this pathogenicity island is also found in commensal and probiotic strains of Escherichia coli and in bacterial species colonizing olive trees and the digestive tract of bees. In this review, we summarize the available literature to address the following key questions. What does this genomic island really encode? What explains the extensive dissemination of this genetically mobile element? What do we really know about the biosynthetic and secretory pathways of colibactin? What is its inherent target/function?
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Proteínas de Escherichia coli , Neoplasias , Policetídeos , Animais , Policetídeos/metabolismo , Peptídeos/genética , Peptídeos/metabolismo , Escherichia coli/metabolismo , Proteínas de Escherichia coli/genética , Dano ao DNA , Neoplasias/genéticaRESUMO
Leptospirosis is a globally important neglected zoonotic disease. Previous data suggest that a family of virulence-modifying (VM) proteins (PF07598) is a distinctive feature of group I pathogenic Leptospira that evolved as important virulence determinants. Here, we show that one such VM protein, LA3490 (also known as Q8F0K3), is expressed by Leptospira interrogans serovar Lai, as a secreted genotoxin that is potently cytotoxic to human cells. Structural homology searches using Phyre2 suggested that VM proteins are novel R-type lectins containing tandem N-terminal ricin B-chain-like ß-trefoil domains. Recombinant LA3490 (rLA3490) and an N-terminal fragment, t3490, containing only the predicted ricin B domain, bound to the terminal galactose and N-acetyl-galactosamine residues, asialofetuin, and directly competed for asialofetuin-binding sites with recombinant ricin B chain. t3490 alone was sufficient for binding, both to immobilized asialofetuin and to the HeLa cell surface but was neither internalized nor cytotoxic. Treatment of HeLa cells with rLA3490 led to cytoskeleton disassembly, caspase-3 activation, and nuclear fragmentation, and was rapidly cytolethal. rLA3490 had DNase activity on mammalian and bacterial plasmid DNA. The combination of cell surface binding, internalization, nuclear translocation, and DNase functions indicate that LA3490 and other VM proteins evolved as novel forms of the bacterial AB domain-containing toxin paradigm.
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Unique DNA repair enzymes that provide self-resistance against therapeutically important, genotoxic natural products have been discovered in bacterial biosynthetic gene clusters (BGCs). Among these, the DNA glycosylase AlkZ is essential for azinomycin B production and belongs to the HTH_42 superfamily of uncharacterized proteins. Despite their widespread existence in antibiotic producers and pathogens, the roles of these proteins in production of other natural products are unknown. Here, we determine the evolutionary relationship and genomic distribution of all HTH_42 proteins from Streptomyces and use a resistance-based genome mining approach to identify homologs associated with known and uncharacterized BGCs. We find that AlkZ-like (AZL) proteins constitute one distinct HTH_42 subfamily and are highly enriched in BGCs and variable in sequence, suggesting each has evolved to protect against a specific secondary metabolite. As a validation of the approach, we show that the AZL protein, HedH4, associated with biosynthesis of the alkylating agent hedamycin, excises hedamycin-DNA adducts with exquisite specificity and provides resistance to the natural product in cells. We also identify a second, phylogenetically and functionally distinct subfamily whose proteins are never associated with BGCs, are highly conserved with respect to sequence and genomic neighborhood, and repair DNA lesions not associated with a particular natural product. This work delineates two related families of DNA repair enzymes-one specific for complex alkyl-DNA lesions and involved in self-resistance to antimicrobials and the other likely involved in protection against an array of genotoxins-and provides a framework for targeted discovery of new genotoxic compounds with therapeutic potential. IMPORTANCE Bacteria are rich sources of secondary metabolites that include DNA-damaging genotoxins with antitumor/antibiotic properties. Although Streptomyces produce a diverse number of therapeutic genotoxins, efforts toward targeted discovery of biosynthetic gene clusters (BGCs) producing DNA-damaging agents is lacking. Moreover, work on toxin-resistance genes has lagged behind our understanding of those involved in natural product synthesis. Here, we identified over 70 uncharacterized BGCs producing potentially novel genotoxins through resistance-based genome mining using the azinomycin B-resistance DNA glycosylase AlkZ. We validate our analysis by characterizing the enzymatic activity and cellular resistance of one AlkZ ortholog in the BGC of hedamycin, a potent DNA alkylating agent. Moreover, we uncover a second, phylogenetically distinct family of proteins related to Escherichia coli YcaQ, a DNA glycosylase capable of unhooking interstrand DNA cross-links, which differs from the AlkZ-like family in sequence, genomic location, proximity to BGCs, and substrate specificity. This work defines two families of DNA glycosylase for specialized repair of complex genotoxic natural products and generalized repair of a broad range of alkyl-DNA adducts and provides a framework for targeted discovery of new compounds with therapeutic potential.
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Produtos Biológicos , DNA Glicosilases , Streptomyces , Alquilantes , Antibacterianos/metabolismo , Produtos Biológicos/metabolismo , DNA , Adutos de DNA , DNA Glicosilases/genética , DNA Glicosilases/metabolismo , Mutagênicos , Streptomyces/genética , Streptomyces/metabolismoRESUMO
Epidemiological studies have found an increased incidence of colorectal cancer (CRC) in people who undergo cholecystectomy compared to healthy individuals. After cholecystectomy, bile enters the duodenum directly, unregulated by the timing of meals. Disruption of the balance of bile acid metabolism and increased production of primary bile acids, which in turn affects the composition and abundance of intestinal microorganisms. The link among cholecystectomy, the gut microbiota, and the occurrence and development of CRC is becoming clearer. However, due to the complexity of the microbial community, the mechanistic connections are less well understood. In this review, we summarize the changes of gut microbiota after cholecystectomy and illuminate the potential mechanisms on CRC, such as inflammation and immune regulation, production of genotoxins, metabolism of dietary ingredients, activation of signaling pathways, and so on. By reviewing these, we aimed to unravel the interactions between the gut microbiota and its host and be better positioned to develop treatments for CRC after cholecystectomy.