Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis最新文献

{"title":"DinB (DNA polymerase IV), ImuBC and RpoS contribute to the generation of ciprofloxacin-resistance mutations in Pseudomonas aeruginosa","authors":"Declan Fahey ,&nbsp;James O’Brien ,&nbsp;Joanne Pagnon ,&nbsp;Simone Page ,&nbsp;Richard Wilson ,&nbsp;Nic Slamen ,&nbsp;Louise Roddam ,&nbsp;Mark Ambrose","doi":"10.1016/j.mrfmmm.2023.111836","DOIUrl":"10.1016/j.mrfmmm.2023.111836","url":null,"abstract":"<div><p>We investigated the role(s) of the damage-inducible SOS response <em>dinB</em> and <em>imuBC</em> gene products in the generation of ciprofloxacin-resistance mutations in the important human opportunistic bacterial pathogen, <em>Pseudomonas aeruginosa</em>. We found that the overall numbers of ciprofloxacin resistant (Cip^R) mutants able to be recovered under conditions of selection were significantly reduced when the bacterial cells concerned carried a defective <em>dinB</em> gene, but could be elevated to levels approaching wild-type when these cells were supplied with the <em>dinB</em> gene on a plasmid vector; in turn, firmly establishing a role for the <em>dinB</em> gene product, error-prone DNA polymerase IV, in the generation of Cip^R mutations in <em>P</em>. <em>aeruginosa</em>. Further, we report that products of the SOS-regulated <em>imuABC</em> gene cassette of this organism, ImuB and the error-prone ImuC DNA polymerase, are also involved in generating Cip^R mutations in this organism, since the yields of Cip^R mutations were substantially decreased in <em>imuB</em>- or <em>imuC</em>-defective cells compared to wild-type. Intriguingly, we found that the mutability of a <em>dinB</em>-defective strain could not be rescued by overexpression of the <em>imuBC</em> genes. And similarly, overexpression of the <em>dinB</em> gene either only modestly or else failed to restore Cip^R mutations in <em>imuB</em>- or <em>imuC</em>-defective cells, respectively. Combined, these results indicated that the products of the <em>dinB</em> and <em>imuBC</em> genes were acting in the same pathway leading to the generation of Cip^R mutations in <em>P</em>. <em>aeruginosa</em>. In addition, we provide evidence indicating that the general stress response sigma factor σ^s, RpoS, is required for mutagenesis in this organism and is in part at least modulating the <em>dinB</em> (DNA polymerase IV)-dependent mutational process. Altogether, these data provide further insight into the complexity and multifaceted control of the mutational mechanism(s) contributing to the generation of ciprofloxacin-resistance mutations in <em>P</em>. <em>aeruginosa</em>.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"827 ","pages":"Article 111836"},"PeriodicalIF":2.3,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10070300","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":"Uncommon variants detected via hereditary cancer panel and suggestions for genetic counseling","authors":"Zeynep Özdemir ,&nbsp;Ezgi Çevik ,&nbsp;Ömür Berna Çakmak Öksüzoğlu ,&nbsp;Mutlu Doğan ,&nbsp;Öztürk Ateş ,&nbsp;Ece Esin ,&nbsp;İrem Bilgetekin ,&nbsp;Umut Demirci ,&nbsp;Çağlar Köseoğlu ,&nbsp;Alper Topal ,&nbsp;Nuri Karadurmuş ,&nbsp;Haktan Bağış Erdem ,&nbsp;Taha Bahsi","doi":"10.1016/j.mrfmmm.2023.111831","DOIUrl":"10.1016/j.mrfmmm.2023.111831","url":null,"abstract":"<div><h3>Objective</h3><p>Hereditary cancer syndromes<span> constitute 5–10% of all cancers. The development of next-generation sequencing technologies has made it possible to examine many hereditary cancer syndrome-causing genes in a single panel. This study's goal was to describe the prevalence and the variant spectrum using NGS in individuals who were thought to have a hereditary predisposition for cancer.</span></p></div><div><h3>Material and method</h3><p>Analysis was performed for 1254 who were thought to have a familial predisposition for cancer. We excluded 46 patients who were carrying <em>BRCA1/2</em><span><span> variants in this study, for focusing on the rare gene mutations. Sequencing was performed using the </span>Sophia<span> Hereditary Cancer Solution v1.1 Panel and the Qiagen Large Hereditary Cancer Panel. The Illumina MiSeq system was used for the sequencing procedure. The software used for the data analyses was Sophia DDM and QIAGEN Clinical Insight (QCITM) Analyze. The resulting genomic changes were classified according to the current guidelines of ACMG/AMP.</span></span></p></div><div><h3>Results</h3><p>Pathogenic/likely pathogenic variants were detected in 172 (13.7%) of 1254 patients. After excluding the 46 <em>BRCA1/2</em><span><span><span>-positive patients, among the remaining 126 patients; there were 60 (4.8%) breast cancer, 33 (2.6%) colorectal cancer, 9 (0.7%) </span>ovarian cancer<span>, 5 (0.4%) endometrium cancer, 5 (0.4%) stomach cancer, 3 (0.2%) </span></span>prostate cancer patients. The most altered genes were </span><span><em>MUTYH</em></span> in 27 (2.1%) patients, MMR genes (<span><span><span><span><em>MLH1</em><em>, </em></span><em>MSH6</em><em>, </em></span><em>MSH</em><span><em>, </em><em>MSH2</em><em>, </em></span></span><em>PMS2</em><em> and EPCAM</em></span>) in 26 (2%) patients, and <em>ATM</em> in 25 (2%) patients. We also examined the genotype-phenotype correlation in rare variants. Additionally, we identified 11 novel variations.</p></div><div><h3>Conclusion</h3><p>This study provided significant information regarding rare variants observed in the Turkish population because it was carried out with a large patient group. Personalized treatment options and genetic counseling for the patients are therefore made facilitated.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"827 ","pages":"Article 111831"},"PeriodicalIF":2.3,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9769666","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":"Lethal and mutagenic effects of different LET radiations on Bacillus subtilis spores","authors":"Katsuya Satoh ,&nbsp;Wataru Hoshino ,&nbsp;Yoshihiro Hase ,&nbsp;Satoshi Kitamura ,&nbsp;Hidenori Hayashi ,&nbsp;Masakazu Furuta ,&nbsp;Yutaka Oono","doi":"10.1016/j.mrfmmm.2023.111835","DOIUrl":"10.1016/j.mrfmmm.2023.111835","url":null,"abstract":"<div><p><span>New, useful microorganism<span> resources have been generated by ionizing radiation<span><span> breeding technology<span>. However, the mutagenic effects of ionizing radiation on microorganisms have not been systematically clarified. For a deeper understanding and characterization of ionizing radiation-induced mutations in microorganisms, we investigated the lethal effects of seven different </span></span>linear energy transfer (LET) radiations based on the survival fraction (SF) and whole-genome sequencing analysis of the mutagenic effects of a dose resulting in an SF of around 1% in </span></span></span><em>Bacillus subtilis</em> spores. Consequently, the lower LET radiations (gamma [surface LET: 0.2 keV/µm] and ⁴He²⁺<span><span> [24 keV/µm]) showed low lethality and high </span>mutation frequency (MF), resulting in the major induction of single-base substitutions. Whereas higher LET radiations (</span>¹²C⁵⁺ [156 keV/µm] and ¹²C⁶⁺ [179 keV/µm]) showed high lethality and low MF, resulting in the preferential induction of deletion mutations. In addition, ¹²C⁶⁺<span><span> (111) ion beams likely possess characteristics of both low- and high-LET radiations simultaneously. A decrease in the </span>relative biological effectiveness and an evaluation of the inactivation cross section indicated that </span>²⁰Ne⁸⁺ (468 keV/µm) and ⁴⁰Ar¹³⁺<span> (2214 keV/µm) ion beams had overkill effects. In conclusion, in the mutation breeding of microorganisms, it should be possible to regulate the proportions, types, and frequencies of induced mutations by selecting an ionizing radiation of an appropriate LET in accordance with the intended purpose.</span></p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"827 ","pages":"Article 111835"},"PeriodicalIF":2.3,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9971357","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":"The E2F1/MELTF axis fosters the progression of lung adenocarcinoma by regulating the Notch signaling pathway","authors":"Lidan Zhang,&nbsp;Lei Shi","doi":"10.1016/j.mrfmmm.2023.111837","DOIUrl":"10.1016/j.mrfmmm.2023.111837","url":null,"abstract":"<div><h3>Background</h3><p><span>Lung adenocarcinoma (LUAD) represents the predominant subtype of lung cancer. MELTF, an </span>oncogene, exhibits high expression in various cancer tissues. Nevertheless, the precise role of MELTF in the progression of LUAD remains enigmatic. This work was devised to investigate the effect of MELTF on LUAD progression and its underlying mechanism.</p></div><div><h3>Methods</h3><p><span>mRNA expression data of LUAD were from The Cancer Genome Atlas database, and the enrichment pathway of MELTF was analyzed. The upstream transcription factors<span> of MELTF were predicted, and the correlation between MELTF and E2F1 as well as the expression of the two in LUAD tissues were dissected by bioinformatics. The expression of MELTF and E2F1 in LUAD tissues and cells was assayed by qRT-PCR. Effects of MELTF/E2F1 on proliferation, migration, and invasion of LUAD cells were tested by CCK-8, colony formation, and Transwell assays. The binding relationship between E2F1 and MELTF was estimated by dual-luciferase reporter gene assay and </span></span>ChIP<span> assay. Western blot was utilized to assay the expression of Notch signaling pathway-related proteins in different treatment groups.</span></p></div><div><h3>Results</h3><p><span>Bioinformatics analysis and qRT-PCR results exhibited high expression of E2F1 and MELTF in LUAD tissues and cells, respectively. Dual-luciferase reporter gene assay and ChIP assay ascertained the binding of E2F1 to MELTF. MELTF was ascertained to enrich the Notch signaling pathway<span> by bioinformatics means. In cell experiments, MELTF was shown to foster the malignant progression of LUAD cells and promoted the expression of NOTCH1 and HES1 proteins, but </span></span>RO4929097 offset the effect of MELTF on cells. Rescue assay confirmed that E2F1 activated MELTF to promote LUAD progression via the Notch signaling pathway.</p></div><div><h3>Conclusion</h3><p>Together, our outcomes demonstrated that E2F1 fostered LUAD progression by activating MELTF via the Notch signaling activity. Hence, MELTF emerged as a feasible target for treating LUAD.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"827 ","pages":"Article 111837"},"PeriodicalIF":2.3,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41224236","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":"Analysis of chemical structures and mutations detected by Salmonella TA98 and TA100","authors":"Kevin P. Cross ,&nbsp;David M. DeMarini","doi":"10.1016/j.mrfmmm.2023.111838","DOIUrl":"10.1016/j.mrfmmm.2023.111838","url":null,"abstract":"<div><p><span>As part of an analysis performed under the auspices of the International Workshop on Genotoxicity Testing (IWGT) in 2017, we and others showed that </span><em>Salmonella</em><span><span> frameshift strain TA98 and base-substitution strain TA100 together + /- S9 detected 93% of the mutagens<span> detected by all the bacterial strains recommended by OECD TG471 (Williams et al., Mutation Res. 848:503081, 2019). We have extended this analysis by identifying the numbers and chemical classes of chemicals detected by these two strains either alone or in combination, including the role of S9. Using the Leadscope 2021 SAR Genetox database containing &gt; 21,900 compounds, our dataset containing 7170 compounds tested in both TA98 and TA100. Together, TA98 and TA100 detected 94% (3733/3981) of the mutagens detected using all the TG471-recommended bacterial strains; 39% were mutagenic in one or both strains. TA100 detected 77% of all of these mutagens and TA98 70%. Considering the overlap of detection by both strains, 12% of these mutagens were detected only by TA98 and 19% only by TA100. In the absence of S9, sensitivity dropped by 31% for TA98 and 29% for TA100. Overall, 32% of the mutagens required S9 for detection by either strain; 9% were detected only without S9. Using the 2021 Leadscope Genetox Expert Alerts, TA100 detected 18 mutagenic alerting chemical classes with better sensitivity than TA98, whereas TA98 detected 10 classes better than TA100. TA100 detected more chemical classes than did TA98, especially </span></span>hydrazines<span><span><span><span>, azides, various di- and tri-halides, various </span>nitrosamines<span>, epoxides<span>, aziridines, difurans, and half-mustards; TA98 especially detected polycyclic primary amines, various </span></span></span>aromatic amines<span>, polycyclic aromatic hydrocarbons, triazines, and dibenzo-furans. Model compounds with these structures induce primarily G to T mutations in TA100 and/or a hotspot GC deletion in TA98. Both TA98 and TA100 + /- S9 are needed for adequate </span></span>mutagenicity screening with the </span></span><em>Salmonella</em> (Ames) assay.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"827 ","pages":"Article 111838"},"PeriodicalIF":2.3,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41125372","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":"LncRNA UCA1 could regulate the progression of neuropathic pain by regulating miR-135a-5p","authors":"Bingbing Wu,&nbsp;Xiaogang Zhou","doi":"10.1016/j.mrfmmm.2023.111833","DOIUrl":"10.1016/j.mrfmmm.2023.111833","url":null,"abstract":"<div><h3>Background</h3><p>Neuropathic pain<span><span> (NPP) is known as a common neurological disease with high incidence rate. The present work focused on the roles of long non-coding RNA </span>urothelial carcinoma antigen 1(LncRNA UCA1) in NPP and the possible underlying mechanism.</span></p></div><div><h3>Methods</h3><p>NPP rat model has been established and the levels of UCA1 NPP as well as the group has been determined by RT-PCR method. Next, NPP rats were treated by UCA1 over-expression plasmid and the behaviors, as well as expression of inflammatory cytokines have been examined. Furthermore, target miRNA of UCA1, miR-135a-5p, has been predicted by bioinformatic method, and further verified with the dual-luciferase reporter assay. Finally, the effects of UCA1/ miR-135a-5p axis have been further evaluated.</p></div><div><h3>Results</h3><p>Expressions of UCA1 were markedly decreased and miR-135a-5p were significantly increased in NPP rats in comparison with the control rats. Over-expression of UCA1 alleviated the inflammatory condition in NPP model by decreasing expression of inflammatory cytokines. miR-135a-5p was confirmed to be a target microRNA of UCA1, and UCA1 may regulate the progress of NPP via targeting miR-135a-5p.</p></div><div><h3>Conclusion</h3><p>UCA1 could regulate NPP via affecting miR-135a-5p expression.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"827 ","pages":"Article 111833"},"PeriodicalIF":2.3,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10210898","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":"Hsa-miR-1269a up-regulation fosters the malignant progression of esophageal squamous cell carcinoma via targeting FAM46C","authors":"Yuefeng Ma ,&nbsp;Xin Xing ,&nbsp;Chuantao Cheng ,&nbsp;Ranran Kong ,&nbsp;Liangzhang Sun ,&nbsp;Feng Zhao ,&nbsp;Danjie Zhang ,&nbsp;Jianzhong Li","doi":"10.1016/j.mrfmmm.2023.111832","DOIUrl":"10.1016/j.mrfmmm.2023.111832","url":null,"abstract":"<div><p>Esophageal squamous cell carcinoma<span> (ESCC) is a malignancy of the alimentary tract resulting in death worldwide. The role and underlying mechanism of hsa-miR-1269a in the progression of ESCC remain unclear. In this study, hsa-miR-1269a was screened by differential expression analysis in TCGA, and its target gene FAM46C was predicted. qRT-PCR was conducted to assay the expression of hsa-miR-1269a and FAM46C in ESCC cells. The results showed that hsa-miR-1269a was upregulated in ESCC tissues and cell lines. Hsa-miR-1269a overexpression stimulated the proliferation, migration, and invasion capacities of ESCC cells, and FAM46C overexpression inhibited these phenotypes. Dual-luciferase assay verified that hsa-miR-1269a could target FAM46C. Next, qRT-PCR and western blot demonstrated that hsa-miR-1269a overexpression downregulated FAM46C. Rescue experiments revealed that hsa-miR-1269a accelerated the malignant progression of ESCC through FAM46C down-regulation. These results indicate that the interaction between hsa-miR-1269a and FAM46C plays a regulatory role in driving the malignant progression of ESCC cells, thereby providing a novel molecular mechanism for understanding ESCC.</span></p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"827 ","pages":"Article 111832"},"PeriodicalIF":2.3,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9828240","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":"Identification and validation of long noncoding RNA AC083900.1 and RP11-283C24.1 for prediction of progression of osteosarcoma","authors":"Liangkun Huang ,&nbsp;Wenyi Jin ,&nbsp;Yucheng Bao ,&nbsp;Xiaoshuang Zeng ,&nbsp;Yubiao Zhang ,&nbsp;Jianlin Zhou ,&nbsp;Hao Peng","doi":"10.1016/j.mrfmmm.2023.111828","DOIUrl":"10.1016/j.mrfmmm.2023.111828","url":null,"abstract":"<div><h3>Background</h3><p>The role of cuproptosis, an emerging cell death pathway that makes a remarkable contribution to tumor progression, remains elusive in osteosarcoma<span> (OS), in addition to its regulator, including long-no-coding RNAs (lncRNAs) that are also a critical factor for fueling OS.</span></p></div><div><h3>Methods</h3><p>Transcriptome and clinical data from 70 normal human bone tissue samples and 84 frozen clinical osteosarcoma samples were included in this study. Cuproptosis-associated lncRNAs (CRlncs) were identified through differential expression and co-expression analyses. Univariate Cox regression was performed to screen for prognostic lncRNAs, then we used least absolute shrinkage and selection operator regression to distinguish prognosis-related CRlncs (AC083900.1 and RP11-283C24.1) for modeling the CRlncs prognostic signature (CLPS) by multivariate Cox regression using the stepwise method. CLPS performance was tested by independent prognostic analyses, survival curve and receiver operating characteristic (ROC) curve. In addition, the molecular and immune mechanisms that underlie the unfavorable prognosis of CLPS-identified high-risk group were elucidated.</p></div><div><h3>Result</h3><p><span><span>AC083900.1 and RP11–283C24.1 have been identified as the most important CRlncs for OS progression (hazard ratio: 3.498 and 2.724, respectively), and the derived CLPS demonstrated outstanding performance for the prediction of OS prognosis (AUC of 0.799 and 0.778 in the training and test sets, both adj-p &lt; 0.05 in survival curve). As was anticipated, CLPS also outperformed a recent clinical prognostic approach that only achieved an AUC of 0.682 [metastasis]. It is notable that AC083900.1 progressed OS metastasis, evidenced by its high expression in metastatic OS, its high correlation to metastasis-related genes, and its high AUC of 0.683 for the prediction of metastasis. Mechanistically, AC083900.1 and RP11–283C24.1 dysregulated many critical biological processes regarding </span>humoral immune response, immunoglobulin complex, etc.; while reducing the </span>infiltration<span> of many cytotoxic immune cells<span> (B-cells, TIL, neutrophils, etc.). It is encouraging that BMS-509744 and KIN001–135 demonstrated high therapeutic implications for CLPS-identified high-risk OS, and the low-risk counterpart was sensitive to SB-216763. Quantitative RT-PCR analysis showed that both AC083900.1 and RP11-283C24.1 were significantly upregulated in different osteosarcoma cell lines.</span></span></p></div><div><h3>Conclusion</h3><p>This study elucidated the roles and mechanisms of AC083900.1 and RP11-283C24.1 in the development of OS, fostering a reliable prognostic approach and treatment for OS patients.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"827 ","pages":"Article 111828"},"PeriodicalIF":2.3,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9776208","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":"Bioinformatics analysis to identify breast cancer-related potential targets and candidate small molecule drugs","authors":"Huan Hong ,&nbsp;Haifeng Chen ,&nbsp;Junjie Zhao ,&nbsp;Long Qin ,&nbsp;Hongrui Li ,&nbsp;Haibo Huo ,&nbsp;Suqiang Shi","doi":"10.1016/j.mrfmmm.2023.111830","DOIUrl":"10.1016/j.mrfmmm.2023.111830","url":null,"abstract":"<div><h3>Objective</h3><p>The purpose of this study is to identify potential targets associated with breast cancer and screen potential small molecule drugs using bioinformatics analysis.</p></div><div><h3>Methods</h3><p><span><span>DEGs analysis of breast cancer tissues and normal breast tissues was performed using R language limma analysis on the GSE42568 and GSE205185 datasets. Functional enrichment analysis was conducted on the intersecting DEGs. The STRING analysis platform was used to construct a PPI network<span>, and the top 10 core nodes were identified using Cytoscape software. QuartataWeb was utilized to build a target-drug interaction network and identify potential drugs. Cell survival and proliferation were assessed using CCK8 and colony formation assays. </span></span>Cell cycle analysis<span> was performed using flow cytometry. Western blot analysis was conducted to assess protein levels of </span></span>PLK1, MELK, AURKA, and NEK2.</p></div><div><h3>Results</h3><p>A total of 54 genes were consistently upregulated in both datasets, which were functionally enriched in mitotic cell cycle and cell cycle-related pathways. The 226 downregulated genes were functionally enriched in pathways related to hormone level regulation and negative regulation of cell population proliferation. Ten key genes, namely <span><em>CDK1, CCNB2, ASPM, AURKA, </em><em>TPX2</em><span><span><span><em>, </em><em>TOP2A</em><em>, </em></span><em>BUB1B</em><em>, MELK, </em></span><em>RRM2</em><em>,</em></span></span> and <em>NEK2</em><span> were identified. The potential drug Fostamatinib was predicted to target AURKA, MELK, CDK1, and NEK2. </span><em>In vitro</em> experiments demonstrated that Fostamatinib inhibited the proliferation of breast cancer cells, induced cell arrest in the G2/M phase, and down-regulated MELK, AURKA, and NEK2 proteins.</p></div><div><h3>Conclusion</h3><p>In conclusion, Fostamatinib shows promise as a potential drug for the treatment of breast cancer by regulating the cell cycle and inhibiting the proliferation of breast cancer cells.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"827 ","pages":"Article 111830"},"PeriodicalIF":2.3,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9776212","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":"Chronic treatment with ATR and CHK1 inhibitors does not substantially increase the mutational burden of human cells","authors":"Lisa Casimir ,&nbsp;Samuel Zimmer ,&nbsp;Félix Racine-Brassard ,&nbsp;Félix Goudreau ,&nbsp;Pierre-Étienne Jacques ,&nbsp;Alexandre Maréchal","doi":"10.1016/j.mrfmmm.2023.111834","DOIUrl":"10.1016/j.mrfmmm.2023.111834","url":null,"abstract":"<div><p><span><span><span>DNA replication stress (RS) entails the frequent slow down and arrest of replication forks by a variety of conditions that hinder accurate and processive genome duplication. Elevated RS leads to </span>genome instability, replication catastrophe and eventually cell death. RS is particularly prevalent in cancer cells and its exacerbation to unsustainable levels by chemotherapeutic agents remains a cornerstone of cancer treatments. The adverse consequences of RS are normally prevented by the ATR and CHK1 checkpoint kinases that stabilize stressed forks, suppress origin firing and promote </span>cell cycle arrest<span> when replication is perturbed. Specific inhibitors of these kinases have been developed and shown to potentiate RS and cell death in multiple in vitro cancer settings. Ongoing clinical trials are now probing their efficacy against various cancer types, either as single agents or in combination with mainstay chemotherapeutics. Despite their promise as valuable additions to the anti-cancer pharmacopoeia, we still lack a genome-wide view of the potential </span></span>mutagenicity<span><span> of these new drugs. To investigate this question, we performed chronic long-term treatments of TP53-depleted human cancer cells with ATR and CHK1 inhibitors (ATRi, AZD6738/ceralasertib and CHK1i, MK8776/SCH-900776). ATR or CHK1 inhibition did not significantly increase the mutational burden of cells, nor generate specific mutational signatures. Indeed, no notable changes in the numbers of base substitutions, short insertions/deletions and larger scale rearrangements were observed despite induction of replication-associated DNA breaks during treatments. Interestingly, ATR inhibition did induce a slight increase in closely-spaced mutations, a feature previously attributed to translesion </span>synthesis DNA<span> polymerases. The results suggest that ATRi and CHK1i do not have substantial mutagenic effects in vitro when used as standalone agents.</span></span></p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"827 ","pages":"Article 111834"},"PeriodicalIF":2.3,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9927248","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}