Mutagenesis最新文献

{"title":"Defective DNA repair: a putative nexus linking immunological diseases, neurodegenerative disorders, and cancer.","authors":"Safaa Andarawi, Ludmila Vodickova, Anusha Uttarilli, Petr Hanak, Pavel Vodicka","doi":"10.1093/mutage/geae029","DOIUrl":"10.1093/mutage/geae029","url":null,"abstract":"<p><p>DNA damage is a common event in cells, resulting from both internal and external factors. The maintenance of genomic integrity is vital for cellular function and physiological processes. The inadequate repair of DNA damage results in the genomic instability, which has been associated with the development and progression of various human diseases. Accumulation of DNA damage can lead to multiple diseases, such as neurodegenerative disorders, cancers, immune deficiencies, infertility, and ageing. This comprehensive review delves the impact of alterations in DNA damage response genes (DDR) and tries to elucidate how and to what extent the same traits modulate diverse major human diseases, such as cancer, neurodegenerative diseases, and immunological disorders. DDR is apparently the trait connecting important complex disorders in humans. However, the pathogenesis of the above disorders and diseases are different and lead to divergent consequences. It is important to discover the switch(es) that direct further the pathogenic process either to proliferative, or degenerative diseases. Our understanding of the influence of DNA damage on diverse human disorders may enable the development of the strategies to prevent, diagnose, and treat these diseases. In our article, we analysed publicly available GWAS summary statistics from the NHGRI-EBI GWAS Catalog and identified 12 009 single-nucleotide polymorphisms (SNPs) associated with cancer. Among these, 119 SNPs were found in DDR pathways, exhibiting significant P-values. Additionally, we identified 44 SNPs linked to various cancer types and neurodegenerative diseases (NDDs), including four located in DDR-related genes: ATM, CUX2, and WNT3. Furthermore, 402 SNPs were associated with both cancer and immunological disorders, with two found in the DDR gene RAD51B. This highlights the versatility of the DDR pathway in multifactorial diseases. However, the specific mechanisms that regulate DDR to initiate distinct pathogenic processes remain to be elucidated.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":"4-19"},"PeriodicalIF":4.3,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399514","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":"Commentary: Special Issue: Current Understanding of Colorectal and Pancreatic Cancers.","authors":"Pavel Vodicka, Ludmila Vodickova","doi":"10.1093/mutage/geae009","DOIUrl":"10.1093/mutage/geae009","url":null,"abstract":"","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":"1-3"},"PeriodicalIF":2.5,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11911007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140326883","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":"Genetic and environmental associations of nonspecific chromosomal aberrations.","authors":"Kari Hemminki, Yasmeen Niazi, Ludmila Vodickova, Pavel Vodicka, Asta Försti","doi":"10.1093/mutage/geae006","DOIUrl":"10.1093/mutage/geae006","url":null,"abstract":"<p><p>Nonspecific structural chromosomal aberrations (CAs) are found in around 1% of circulating lymphocytes from healthy individuals but the frequency may be higher after exposure to carcinogenic chemicals or radiation. CAs have been used in the monitoring of persons exposed to genotoxic agents and radiation. Previous studies on occupationally exposed individuals have shown associations between the frequency of CAs in peripheral blood lymphocytes and subsequent cancer risk. The cause for CA formation is believed to be unrepaired or insufficiently repaired DNA double-strand breaks or other DNA damage, and additionally telomere shortening. CAs include chromosome (CSAs) and chromatid type aberrations (CTAs). In the present review, we first describe the types of CAs, the conventional techniques used for their detection and some aspects of interpreting the results. We then focus on germline genetic variation in the frequency and type of CAs measured in a genome-wide association study in healthy individuals in relation to occupational and smoking-related exposure compared to nonexposed referents. The associations (at P < 10-5) on 1473 healthy individuals were broadly classified in candidate genes from functional pathways related to DNA damage response/repair, including PSMA1, UBR5, RRM2B, PMS2P4, STAG3L4, BOD1, COPRS, and FTO; another group included genes related to apoptosis, cell proliferation, angiogenesis, and tumorigenesis, COPB1, NR2C1, COPRS, RHOT1, ITGB3, SYK, and SEMA6A; a third small group mapped to genes KLF7, SEMA5A and ITGB3 which were related to autistic traits, known to manifest frequent CAs. Dedicated studies on 153 DNA repair genes showed associations for some 30 genes, the expression of which could be modified by the implicated variants. We finally point out that monitoring of CAs is so far the only method of assessing cancer risk in healthy human populations, and the use of the technology should be made more attractive by developing automated performance steps and incorporating artificial intelligence methods into the scoring.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":"30-38"},"PeriodicalIF":4.3,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11911008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139996878","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":"Tribute to Professor Diana Anderson: A scientist extra ordinaire (11.12.1940 - 11.10.2024).","authors":"Alok Dhawan","doi":"10.1093/mutage/geaf002","DOIUrl":"https://doi.org/10.1093/mutage/geaf002","url":null,"abstract":"","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008608","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":"Exploring the relationship between genetic instability and health outcomes in acute and chronic post-COVID syndrome.","authors":"Bruna Alves Alonso Martins, Ana Leticia Hilario Garcia, Malu Siqueira Borges, Juliana Picinini, Enaile Tuliczewski Serpa, Daiane Dias Ribeiro Nobles, Luana Letícia Silva, Daiana Dalberto, Alana Witt Hansen, Fernando Rosado Spilki, Lavínia Schuler-Faccini, Pabulo Henrique Rampelotto, Juliana Da Silva","doi":"10.1093/mutage/geae022","DOIUrl":"10.1093/mutage/geae022","url":null,"abstract":"<p><p>The COVID-19 pandemic has led to the emergence of acute and chronic post-COVID syndromes, which present diverse clinical manifestations. The underlying pathophysiology of these conditions is not yet fully understood, but genetic instability has been proposed as a potential contributing factor. This study aimed to explore the differential impact of physical and psychological health factors on genetic instability in individuals with acute and chronic post-COVID syndromes. In this study, three groups of subjects were analyzed: a control group, an acute post-COVID group, and a chronic post-COVID group, with a total of 231 participants. The participants were assessed using a questionnaire for long-COVID-19COVID, and female participants reported more symptoms than male participants in areas related to fatigue, memory, mental health, and well-being during the chronic phase. Genetic instability was assessed using the comet assay, and participants' physical and psychological profiles were evaluated. The overall results showed no significant differences in DNA damage, as measured by the comet assay, among the three groups, suggesting that genetic instability, as assessed by this method, may not be a primary driver of the distinct clinical presentations observed in post-COVID syndromes. However, when gender was considered, male participants in the acute long COVID group exhibited higher levels of genetic instability compared to females. Multiple linear regression analysis revealed that gender, age, and waist circumference were significant predictors of DNA damage. Among females in the acute group, sexual health, and eye-related symptoms significantly influenced the increase in DNA damage. These findings indicate the need for further investigation on the gender-specific differences in genetic instability and their potential implications for the pathophysiology of post-COVID syndromes. Exploring alternative markers of genetic instability and the interplay between genetic, inflammatory, and cellular processes could provide valuable insights for the management of these debilitating post-viral sequelae.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":"287-300"},"PeriodicalIF":4.3,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109654","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":"Piper auritum ethanol extract is a potent antimutagen against food-borne aromatic amines: mechanisms of action and chemical composition.","authors":"Sandra L Hernández-Ojeda, Javier Jesús Espinosa-Aguirre, Rafael Camacho-Carranza, Jessica Amacosta-Castillo, Ricardo Cárdenas-Ávila","doi":"10.1093/mutage/geae011","DOIUrl":"10.1093/mutage/geae011","url":null,"abstract":"<p><p>An ethanol extract of Piper auritum leaves (PAEE) inhibits the mutagenic effect of three food-borne aromatic amines (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP); 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx); 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-DiMeIQx)) in the TA98 Salmonella typhimurium strain. Preincubation with MeIQx demonstrated in mutagenesis experiments that inhibition of Cytochrome P450 (CYP), as well as direct interaction between component(s) of the plant extract with mutagens, might account for the antimutagenic observed effect. Gas chromatography/mass spectrometry analysis revealed that safrole (50.7%), α-copaene (7.7%), caryophyllene (7.2%), β-pinene (4.2%), γ-terpinene (4.1%), and pentadecane (4.1%) as the main components (PAEE). Piper extract and safrole were able to inhibit the rat liver microsomal CYP1A1 activity that participates in the amines metabolism, leading to the formation of the ultimate mutagenic/ molecules. According to this, safrole and PAEE-inhibited MeIQx mutagenicity but not that of the direct mutagen 2-nitrofluorene. No mutagenicity of plant extract or safrole was detected. This study shows that PAEE and its main component safrole are associated with the inhibition of heterocyclic amines activation due in part to the inhibition of CYP1A subfamily activity.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":"301-309"},"PeriodicalIF":4.3,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140194216","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":"Cyto- and genotoxicity evaluation of water samples collected from two rivers in the Kosovo.","authors":"Fisnik H Asllani, Avdulla J Alija, Peter M Eckl, Nikolaus Bresgen","doi":"10.1093/mutage/geae019","DOIUrl":"10.1093/mutage/geae019","url":null,"abstract":"<p><p>River water in Kosovo is exposed to various discharges from industrial and agricultural activities as well as to urban wastewater. Rivers Sitnica and Drenica are among the most affected ones and water samples drawn from these rivers show the presence of various toxic substances. Genotoxic effects are seen in fish living in these rivers indicating a cytotoxic and mutagenic potential of the river water. Aiming at substantiating these observations, we assessed the cyto- and genotoxic effects of water samples collected at different locations from the Drenica and Sitnica rivers. Samples drawn from Lake Badovc served for comparison. To address seasonal effects, samples were collected at different seasons/time points during the period of summer 2016-spring 2018. The water samples were analyzed employing primary rat hepatocytes as a reliable in vitro cell model for the assessment of cytotoxic effects (mitotic arrest and cell death) and DNA damage/genotoxicity (micronucleus assay and Comet assay). The results do not account for significant effects associated with specific locations but demonstrate seasonal differences of the genotoxic potential of the water samples collected along both rivers, which are accompanied by a limited cytotoxic potential. Our data provide substantial support to earlier observations and strongly warrant the need for continuous chemical as well as biological monitoring of the river water in Kosovo, focusing on improved toxicant profiling of the river water and investigations addressing the observed seasonal variations.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":"310-317"},"PeriodicalIF":4.3,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141907078","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":"Expression of Concern: Divergent molecular profile of PIK3CA gene in arsenic-associated bladder carcinoma.","authors":"","doi":"10.1093/mutage/geae016","DOIUrl":"10.1093/mutage/geae016","url":null,"abstract":"","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":"327"},"PeriodicalIF":2.5,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141545047","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":"Impact of DNA ligase inhibition on the nick sealing of polβ nucleotide insertion products at the downstream steps of base excision repair pathway.","authors":"Danah Almohdar, Pradnya Kamble, Chandrakala Basavannacharya, Mitchell Gulkis, Ozlem Calbay, Shuang Huang, Satya Narayan, Melike Çağlayan","doi":"10.1093/mutage/geae013","DOIUrl":"10.1093/mutage/geae013","url":null,"abstract":"<p><p>DNA ligase (LIG) I and IIIα finalize base excision repair (BER) by sealing a nick product after nucleotide insertion by DNA polymerase (pol) β at the downstream steps. We previously demonstrated that a functional interplay between polβ and BER ligases is critical for efficient repair, and polβ mismatch or oxidized nucleotide insertions confound the final ligation step. Yet, how targeting downstream enzymes with small molecule inhibitors could affect this coordination remains unknown. Here, we report that DNA ligase inhibitors, L67 and L82-G17, slightly enhance hypersensitivity to oxidative stress-inducing agent, KBrO3, in polβ+/+ cells more than polβ-/- null cells. We showed less efficient ligation after polβ nucleotide insertions in the presence of the DNA ligase inhibitors. Furthermore, the mutations at the ligase inhibitor binding sites (G448, R451, A455) of LIG1 significantly affect nick DNA binding affinity and nick sealing efficiency. Finally, our results demonstrated that the BER ligases seal a gap repair intermediate by the effect of polβ inhibitor that diminishes gap filling activity. Overall, our results contribute to understand how the BER inhibitors against downstream enzymes, polβ, LIG1, and LIGIIIα, could impact the efficiency of gap filling and subsequent nick sealing at the final steps leading to the formation of deleterious repair intermediates.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":"263-279"},"PeriodicalIF":4.3,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140912533","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":"Determination of global DNA methylation level by methylation-sensitive comet assay in patients with urinary bladder cancer.","authors":"Ozer Kocak, Selin Kankaya, Goktug Kalender, Sinharib Citgez, Bulent Onal, Yildiz Dincer","doi":"10.1093/mutage/geae018","DOIUrl":"10.1093/mutage/geae018","url":null,"abstract":"<p><p>DNA methylation is an important mechanism in the regulation of gene expression and maintenance of genomic integrity. Aberrant DNA methylation is an early event in carcinogenesis. DNA methyltransferase inhibitors are used to restore aberrant DNA methylation and inhibit tumor growth. Evaluation of DNA methylation level is important for an effective anti-cancer therapy. In the present study, the determination of global DNA methylation levels in patients with urinary bladder cancer was proposed. The methylation-sensitive comet assay determined the global DNA methylation level at the level of single cells. McrBC enzyme, a methylation-sensitive restriction endonuclease, was used for enzymatic digestion to generate additional breaks at methylated sites. % DNA methylation level was significantly higher in patients with bladder cancer compared to the control group. The clinical performance of % DNA methylation analysis by methylation-sensitive comet assay was evaluated by ROC curve. Using the cutoff value of 6.5% DNA methylation, 92% sensitivity, and 42% specificity were obtained. In conclusion, global DNA methylation measured by methylation-sensitive comet assay may be a promising noninvasive biomarker that reduces interventional tests required in the diagnosis and follow-up of urinary bladder cancer.</p>","PeriodicalId":18889,"journal":{"name":"Mutagenesis","volume":" ","pages":"280-286"},"PeriodicalIF":4.3,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141913317","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}