Mutation research. Genetic toxicology and environmental mutagenesis最新文献

{"title":"Cytotoxic and genotoxic profiles of the pyrethroid insecticide lambda-cyhalothrin and its microformulation Karate® in CHO-K1 cells","authors":"Milagros R.R. Laborde ,&nbsp;Marcelo L. Larramendy ,&nbsp;Sonia Soloneski","doi":"10.1016/j.mrgentox.2023.503682","DOIUrl":"10.1016/j.mrgentox.2023.503682","url":null,"abstract":"<div><p>Lambda-cyhalothrin (LCT) and its microformulation Karate® (25 % a.i.) were analysed for its genotoxicity and cytotoxicity on Chinese hamster ovary (CHO-K1) cells. Cytokinesis-block micronucleus cytome (CBMN-cyt) and alkaline single-cell gel electrophoresis (SCGE) bioassays were selected to test genotoxicity. Neutral red uptake (NRU), succinic dehydrogenase activity (MTT) and apoptogenic induction were employed for estimating cytotoxicity. Both compounds were analysed within a concentration range of 0.1–100 µg/mL. Only LCT produced a significant augment in the frequency of micronuclei (MNs) when the cultures were exposed to highest concentrations of 10 and 100 µg LCT/mL. A noticeable decrease in NDI was observed for cultures treated with LCT at 10 and 100 µg/mL. Karate® induced the inhibition of both the proportion of viable cells and succinic dehydrogenase activity and triggered apoptosis 24 h of exposition. Whilst an increased GDI in CHO-K1 cells was observed in the treatments with 1–100 µg Karate®/mL, the GDI was not modified in the treatments employing LCT at equivalent doses. SCGE showed that Karate® was more prone to induce genotoxic effects than LCT. Only 50 µg/mL of Karate® was able to increase apoptosis. Our results demonstrate the genomic instability and cytotoxic effects induced by this pyrethroid insecticide, confirming that LCT exposure can result in a severe drawback for the ecological equilibrium of the environment.</p></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"891 ","pages":"Article 503682"},"PeriodicalIF":1.9,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41100986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blood molecular profile to predict genotoxicity from exposure to antineoplastic drugs","authors":"Carina Ladeira ,&nbsp;Rúben Araújo ,&nbsp;Luís Ramalhete ,&nbsp;Hélder Teixeira ,&nbsp;Cecília R.C. Calado","doi":"10.1016/j.mrgentox.2023.503681","DOIUrl":"10.1016/j.mrgentox.2023.503681","url":null,"abstract":"<div><p>Genotoxicity is an important information that should be included in human biomonitoring programmes. However, the usually applied cytogenetic assays are laborious and time-consuming, reason why it is critical to develop rapid and economic new methods. The aim of this study was to evaluate if the molecular profile of frozen whole blood, acquired by Fourier Transform Infrared (FTIR) spectroscopy, allows to assess genotoxicity in occupational exposure to antineoplastic drugs, as obtained by the cytokinesis-block micronucleus assay. For that purpose, 92 samples of peripheral blood were studied: 46 samples from hospital professionals occupationally exposed to antineoplastic drugs and 46 samples from workers in academia without exposure (controls). It was first evaluated the metabolome from frozen whole blood by methanol precipitation of macromolecules as haemoglobin, followed by centrifugation. The metabolome molecular profile resulted in 3 ratios of spectral bands, significantly different between the exposed and non-exposed group (p &lt; 0.01) and a spectral principal component-linear discriminant analysis (PCA-LDA) model enabling to predict genotoxicity from exposure with 73 % accuracy. After optimization of the dilution degree and solution used, it was possible to obtain a higher number of significant ratios of spectral bands, <em>i.e.</em>, 10 ratios significantly different (p &lt; 0.001), highlighting the high sensitivity and specificity of the method. Indeed, the PCA-LDA model, based on the molecular profile of whole blood, enabled to predict genotoxicity from the exposure with an accuracy, sensitivity, and specificity of 92 %, 93 % and 91 %, respectively. All these parameters were achieved based on 1 μL of frozen whole blood, in a high-throughput mode, <em>i.e.</em>, based on the simultaneous analysis of 92 samples, in a simple and economic mode. In summary, it can be conclude that this method presents a very promising potential for high-dimension screening of exposure to genotoxic substances.</p></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"891 ","pages":"Article 503681"},"PeriodicalIF":1.9,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41134857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In silico prediction of the mutagenicity of nitroaromatic compounds using correlation weights of fragments of local symmetry","authors":"Andrey A. Toropov,&nbsp;Alla P. Toropova,&nbsp;Alessandra Roncaglioni,&nbsp;Emilio Benfenati","doi":"10.1016/j.mrgentox.2023.503684","DOIUrl":"10.1016/j.mrgentox.2023.503684","url":null,"abstract":"<div><p>Most quantitative structure-property/activity relationships (QSPRs/QSARs) techniques involve using different programs separately for generating molecular descriptors and separately for building models based on available descriptors. Here, the capabilities of the CORAL program are evaluated. A user of the program should apply as the basis for models the representation of the molecular structure by means of the simplified molecular input-line entry system (SMILES) as well as experimental data on the endpoint of interest. The local symmetry of SMILES is a novel composition of symmetrically represented symbols, which are three ‘<em>xyx</em>’, four ‘<em>xyyx</em>’, or five symbols ‘<em>xyzyx</em>’. We updated our CORAL software using this optimal, new flexible descriptor, sensitive to the symmetric composition of a specific part of the molecule. Computational experiments have shown that taking account of these attributes of SMILES can improve the predictive potential of models for the mutagenicity of nitroaromatic compounds. In addition, the above computational experiments have confirmed the advantage of using the index of ideality of correlation (<em>IIC</em>) and the correlation intensity index (<em>CII</em>) for Monte Carlo optimization of the correlation weights for various attributes of SMILES, including the local symmetry. The average value of the coefficient of determination for the validation set (five different models) without fragments of local symmetry is 0.8589 ± 0.025, whereas using fragments of local symmetry improves this criterion of the predictive potential up to 0.9055 ± 0.010.</p></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"891 ","pages":"Article 503684"},"PeriodicalIF":1.9,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41134932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole-genome high-fidelity sequencing: A novel approach to detecting and characterization of mutagenicity in vivo","authors":"Vasily N. Dobrovolsky ,&nbsp;Tomonari Matsuda ,&nbsp;Page McKinzie ,&nbsp;Jaime Miranda ,&nbsp;Javier R. Revollo","doi":"10.1016/j.mrgentox.2023.503691","DOIUrl":"10.1016/j.mrgentox.2023.503691","url":null,"abstract":"<div><p>Direct DNA sequencing can be used for characterizing mutagenicity in simple and complex biological models. Recently we described a method of whole-genome sequencing for detecting mutations in simple models of cultured bacteria, mammalian cells, and nematode. In the current proof-of-concept study, we expand and improve our method for evaluating a more complex mammalian biological model in outbred mice. We detail the method by applying it to a small set of animals treated with a mutagen with known mutagenicity profiles, <em>N</em>-ethyl-<em>N</em>-nitrosourea (ENU), for consistency with the known data. Whole-genome high-fidelity sequencing (HiFi Sequencing) showed frequencies and spectra of background mutations in tissues of untreated mice that were consistent with normal ageing and characterized by spontaneous or enzymatic deamination of 5-methylcytosine. In mice treated with a single 40 mg/kg dose of ENU, the frequency of mutations in the genomic DNA of solid tissues increased up to 7-fold, with the greatest increase observed in the spleen and the smallest increase in the liver. The most common mutations detected in ENU-treated mice were T &gt; A transitions and T &gt; C transversions, consistent with the types of mutations caused by alkylating agents. The data suggest that HiFi Sequencing may be useful for characterizing mutagenicity of novel compounds in various biological models.</p></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"891 ","pages":"Article 503691"},"PeriodicalIF":1.9,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41155655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation and interpretation of cytogenetic test results based on biological relevance","authors":"Makoto Hayashi","doi":"10.1016/j.mrgentox.2023.503693","DOIUrl":"10.1016/j.mrgentox.2023.503693","url":null,"abstract":"<div><p>The evaluation and interpretation of cytogenetic test data are discussed from the perspective of biological relevance. The reliability of tests must be considered, before evaluation and interpretation. Statistical procedures are important for the evaluation of test data, but for human health risk assessment, biological relevance is essential. Cell culture conditions must be carefully considered. Cells must be healthy in the physiologically controlled culture medium. Osmolality, pH, and temperature are critical factors in keeping the culture medium physiologically normal and avoiding artifactual responses. Careful attention must be paid to the exposure of test chemicals to target cells, in both <em>in vitro</em> and <em>in vivo</em> tests. For <em>in vivo</em> tests, absorption, distribution, metabolism, and excretion are critical issues that affect the exposure of the target cells to the test chemical. The dose-response relationship and reproducibility are also critical factors in biological reliability. I also discuss why so many chemicals show positive results in <em>in vitro</em> cytogenetic assays.</p></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"891 ","pages":"Article 503693"},"PeriodicalIF":1.9,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41127085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alteration of genome-wide DNA methylation in non-uranium miners induced by high level radon exposure","authors":"Pinhua Zhang ,&nbsp;Yunyun Wu ,&nbsp;Chunnan Piao ,&nbsp;Yanchao Song ,&nbsp;Yanfang Zhao ,&nbsp;Yumin Lyu ,&nbsp;Quanfu Sun ,&nbsp;Jianxiang Liu","doi":"10.1016/j.mrgentox.2023.503683","DOIUrl":"10.1016/j.mrgentox.2023.503683","url":null,"abstract":"<div><p>In China, according to statistics about underground non-uranium mine radon levels, 15% exceed the national standard intervention level of 1000 Bq/m³, and some mines may exceed 10,000 Bq/m³. The relationship between radon exposure in underground miners and lung cancer has already been established, but the mechanisms and biological processes underlying it are poorly understood. In order to identify the genome-wide DNA methylation profile associated with long-term radon exposure, we performed the Infinium Human Methylation 850 K BeadChip measurement in whole blood samples obtained from 15 underground non-uranium miners and 10 matched aboveground control workers. Radon concentrations in the air of workplaces and living environments were measured by CR-39 radon detectors, and annual effective doses were calculated using the detection data. Under the high radon concentration with an average value of 12,700 Bq·m⁻³, a total of 165 significant differentially methylated positions (127 hypermethylated sites and 38 hypomethylated sites) annotated to 71 genes were identified in underground miners (|Δ<em>β</em>| ≥ 0.10, <em>p</em> &lt; 0.05), and the average DNA methylation level of 165 DMPs was significantly higher than that of the control workers. Most DMPs were found on chromosome 1, and approximately one-quarter of them were located in genomic promoter regions. Through bioinformatics analysis and pyrosequencing validation, five candidate genes differentially methylated by radon, including <em>TIMP2</em>, <em>EMP2</em>, <em>CPT1B</em>, <em>AMD1</em> and <em>SLC43A2</em> were identified. GO and KEGG analysis implicated that long term radon exposure could induce the lung cancer related biological processes such as cell adhesion and cellular polarity maintenance. Our study provides evidence for the alterations of genome-wide DNA methylation profiles induced by long-term high level radon exposure, and new insights into searching for carcinogenic biomarkers of high radon exposure in future studies.</p></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"891 ","pages":"Article 503683"},"PeriodicalIF":1.9,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41133983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Micronuclei in human peripheral blood and bone marrow as genotoxicity markers: A systematic review and meta-analysis","authors":"Evangelia E. Antoniou ,&nbsp;Martijn Rooseboom ,&nbsp;Neslihan A. Kocabas ,&nbsp;Colin M. North ,&nbsp;Maurice P. Zeegers","doi":"10.1016/j.mrgentox.2023.503689","DOIUrl":"10.1016/j.mrgentox.2023.503689","url":null,"abstract":"<div><p>Can human peripheral blood cells be used as a surrogate for bone marrow cells, in evaluating the genotoxic effects of stressors? We searched the Pubmed/Medline and PubChem databases to identify publications relevant to this question. Micronucleus formation was the genotoxicity endpoint. Three publications comparing exposed vs. non-exposed individuals are included in this analysis; the exposures were to ethylene oxide or ionising radiation (atomic bomb, thorotrast, or radioiodine therapy). Information was extracted on the types of exposure, the numbers of participants, and the micronucleus frequencies. Relative differences (odds ratios) and absolute differences (risk differences) in the numbers of micronuclei between exposed and non-exposed persons were calculated separately for individual cell types (peripheral blood and bone marrow). Random effects meta-analyses for the relative differences in cell abnormalities were performed. The results showed very small differences in the frequencies of micronuclei between exposed and non-exposed individuals, as measured in either peripheral blood or bone marrow cell populations, on both absolute and relative scales. No definite conclusion concerning the relative sensitivities of bone marrow and peripheral blood cells can be made, based on these publications.</p></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"891 ","pages":"Article 503689"},"PeriodicalIF":1.9,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41120355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing phytotoxicity and cyto-genotoxicity of two insecticides using a battery of in-vitro biological assays","authors":"Mohammad Shahid ,&nbsp;Mohammad Tarique Zeyad ,&nbsp;Asad Syed ,&nbsp;Ali H. Bahkali ,&nbsp;John Pichtel ,&nbsp;Meenakshi Verma","doi":"10.1016/j.mrgentox.2023.503688","DOIUrl":"10.1016/j.mrgentox.2023.503688","url":null,"abstract":"<div><p>Intensive use of chemical pesticides in agriculture poses environmental risks and may have negative impacts on agricultural productivity. The potential phytotoxicity of two chemical pesticides, chlorpyrifos (CPS) and fensulfothion (FSN), were evaluated using <em>Cicer arietinum</em> and <em>Allium cepa</em> as model crops. Different concentrations (0–100 μgmL^-1) of both CPS and FSN decreased germination and biological attributes of <em>C. arietinum</em>. High pesticide doses significantly (<em>p</em> ≤ 0.05) caused membrane damage by producing thiobarbituric acid reactive substances (TBARS) and increasing proline (<em>Pro</em>) content. Pesticides elevated ROS levels and substantially increased the superoxide anions and H₂O₂ concentrations, thus aggravating cell injury. Plants exposed to high pesticide dosages displayed significantly higher antioxidant levels to combat pesticide-induced oxidative stress. Ascorbate peroxidase (APX), guaiacol peroxidase (GPX), catalase (CAT), peroxidase (POD), and superoxide dismutase (SOD) increased by 48%, 93%, 71%, 52% and 94%, respectively, in <em>C. arietinum</em> roots exposed to 100 µgFSNmL^-1. Under CLSM, pesticide-exposed <em>C. arietinum</em> and 2’,7’-dichlorodihydrofluorescein diacetate (2’7’-DCF) and 3,3’-diaminobenzidine stained roots exhibited increased ROS production in a concentration-dependent manner. Additionally, enhanced Rhodamine 123 (Rhd 123) and Evan's blue fluorescence in roots, as well as changes in mitochondrial membrane potential (ΔΨ<em>m</em>) and cellular apoptosis, were both associated with high pesticide dose. <em>Allium cepa</em> chromosomal aberration (CAs) assay showed a clear reduction in mitotic index (MI) and numerous chromosomal anomalies in root meristematic cells. Additionally, a-dose-dependent increase in DNA damage in root meristematic cells of <em>A. cepa</em> and conversion of the super-coiled form of DNA to open circular in pBR322 plasmid revealed the genotoxic potential of pesticides. The application of CPS and FSN suggests phytotoxic and cyto-genotoxic effects that emphasize the importance of careful monitoring of current pesticide level in soil before application and addition at optimal levels to soil-plant system. It is appropriate to prepare both target-specific and slow-release agrochemical formulations for crop protection with concurrent safeguarding of agroecosystems.</p></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"891 ","pages":"Article 503688"},"PeriodicalIF":1.9,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41134856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adopting duplex sequencing technology for genetic toxicity testing: A proof-of-concept mutagenesis experiment with N-ethyl-N-nitrosourea (ENU)-exposed rats","authors":"Stephanie L. Smith-Roe ,&nbsp;Cheryl A. Hobbs ,&nbsp;Victoria Hull ,&nbsp;J. Todd Auman ,&nbsp;Leslie Recio ,&nbsp;Michael A. Streicker ,&nbsp;Miriam V. Rivas ,&nbsp;Gabriel A. Pratt ,&nbsp;Fang Yin Lo ,&nbsp;Jacob E. Higgins ,&nbsp;Elizabeth K. Schmidt ,&nbsp;Lindsey N. Williams ,&nbsp;Daniela Nachmanson ,&nbsp;Charles C. Valentine III ,&nbsp;Jesse J. Salk ,&nbsp;Kristine L. Witt","doi":"10.1016/j.mrgentox.2023.503669","DOIUrl":"10.1016/j.mrgentox.2023.503669","url":null,"abstract":"<div><p>Duplex sequencing (DS) is an error-corrected next-generation sequencing method in which molecular barcodes informatically link PCR-copies back to their source DNA strands, enabling computational removal of errors in consensus sequences. The resulting background of less than one artifactual mutation per 10⁷ nucleotides allows for direct detection of somatic mutations. TwinStrand Biosciences, Inc. has developed a DS-based mutagenesis assay to sample the rat genome, which can be applied to genetic toxicity testing. To evaluate this assay for early detection of mutagenesis, a time-course study was conducted using male Hsd:Sprague Dawley SD rats (3 per group) administered a single dose of 40 mg/kg N-ethyl-N-nitrosourea (ENU) via gavage, with mutation frequency (MF) and spectrum analyzed in stomach, bone marrow, blood, and liver tissues at 3 h, 24 h, 7 d, and 28 d post-exposure. Significant increases in MF were observed in ENU-exposed rats as early as 24 h for stomach (site of contact) and bone marrow (a highly proliferative tissue) and at 7 d for liver and blood. The canonical, mutational signature of ENU was established by 7 d post-exposure in all four tissues. Interlaboratory analysis of a subset of samples from different tissues and time points demonstrated remarkable reproducibility for both MF and spectrum. These results demonstrate that MF and spectrum can be evaluated successfully by directly sequencing targeted regions of DNA obtained from various tissues⁠, a considerable advancement compared to currently used in vivo gene mutation assays.</p></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"891 ","pages":"Article 503669"},"PeriodicalIF":1.9,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10539650/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41155653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"POT1 involved in telomeric DNA damage repair and genomic stability of cervical cancer cells in response to radiation","authors":"Qian Li ,&nbsp;Xiaofei Wang ,&nbsp;Jie Liu ,&nbsp;Lijun Wu ,&nbsp;Shengmin Xu","doi":"10.1016/j.mrgentox.2023.503670","DOIUrl":"10.1016/j.mrgentox.2023.503670","url":null,"abstract":"<div><p>Though telomeres play a crucial role in maintaining genomic stability in cancer cells and have emerged as attractive therapeutic targets in anticancer therapy, the relationship between telomere dysfunction and genomic instability induced by irradiation is still unclear. In this study, we identified that protection of telomeres 1 (POT1), a single-stranded DNA (ssDNA)-binding protein, was upregulated in γ-irradiated HeLa cells and in cancer patients who exhibit radiation tolerance. Knockdown of POT1 delayed the repair of radiation-induced telomeric DNA damage which was associated with enhanced H3K9 trimethylation and enhanced the radiosensitivity of HeLa cells. The depletion of POT1 also resulted in significant genomic instability, by showing a significant increase in end-to-end chromosomal fusions, and the formation of anaphase bridges and micronuclei. Furthermore, knockdown of POT1 disturbed telomerase recruitment to telomere, and POT1 could interact with phosphorylated ATM (p-ATM) and POT1 depletion decreased the levels of p-ATM induced by irradiation, suggesting that POT1 could regulate the telomerase recruitment to telomeres to repair irradiation-induced telomeric DNA damage of HeLa cells through interactions with p-ATM. The enhancement of radiosensitivity in cancer cells can be achieved through the combination of POT1 and telomerase inhibitors, presenting a potential approach for radiotherapy in cancer treatment.</p></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"891 ","pages":"Article 503670"},"PeriodicalIF":1.9,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41155654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}