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

{"title":"Impact of glutathione S transferases P1 (Ile105Val) variants on the risk of GSTp, phosphorylated c-Jun kinase, and P53 phenotypic expression and their implications on overall survival outcomes in non-small cell lung cancer patients treated with chemotherapy","authors":"Anumesh K. Pathak ,&nbsp;Nuzhat Husain ,&nbsp;Saumya Shukla ,&nbsp;Rahul Kumar Pandey ,&nbsp;Surya Kant ,&nbsp;Lakshmi Bala","doi":"10.1016/j.mrfmmm.2022.111775","DOIUrl":"10.1016/j.mrfmmm.2022.111775","url":null,"abstract":"<div><h3>Aim</h3><p>This study focused on GST-M1, T1 null, and P1 Ile105Val variant genotypes associated with the risk of altered expression of GSTp, pJNK, and P53 in NSCLC patients. These markers and overall survival (OS) were correlated with a key set of clinicopathological characteristics.</p></div><div><h3>Methods</h3><p>Genotyping of GST- M1, T1 (+/−), and P1 (Ile105Val) was performed using PCR-RFLP.The expression of GSTp, pJNK, and P53 phenotypes was assessed by immunohistochemistry. The Spearman test was used to examine the correlation between GSTp, pJNK, and P53. Kaplan-Meier test was used for OS analysis.</p></div><div><h3>Results</h3><p><span>GSTP1<span> Val/Val and Ile/Val genotypes notably increased GSTp expression by 1.8 and 1.7 fold, respectively (p = 0.04,p = 0.06). GSTP1 Val/Val and Ile/Val genotypes considerably reduced P53 expression by 0.61 and 0.57 fold, respectively (p = 0.03&amp; p = 0.05), respectively. GSTp, pJNK, and P53 were significantly co-expressed (p &lt; 0.001). GSTp and pJNK expression showed a moderate negative correlation (ρ = −0.32, p = 0.046). In contrast, GSTp and P53 expression exhibited a strong negative correlation (ρ = −0.53, p &lt; 0.0001). There was no correlation between P53 and pJNK expression(ρ = 0.07, p = 0.54). The patient’s median OS was 8.9 months, and it was significantly related to pack-years, stage, metastasis, and GSTM1(-/-) genotypes (p &gt; 0.05). SQCLC showed poor OS than ADC (5.7 months vs.9.1 months, p = 0.2). Stage IV and metastasis significantly reduced the OS (p = 0.001). The tumour size and lymph nodes<span> reflected poor OS (p = 0.07&amp;p = 0.06). Gemcitabine+Cisplatin and Gefitinib showed a slightly higher rate of survival (9.3 months and 8.1 months) than Pemtrexe+Cisplatin treatment (7.0 months,p = 0.8). </span></span></span>Multivariate analysis revealed that pack-years and GSTp were independent predictors for OS (p = 0.03).</p></div><div><h3>Conclusion</h3><p>GSTp, pJNK, and P53 showed interconnected cascading. Age, pack-year, stage, and GSTp were found to be significant predictive factors for OS.Pack-years, GSTp independent OS predictor.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"824 ","pages":"Article 111775"},"PeriodicalIF":2.3,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39754435","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":"Neutrophils and micronuclei: An emerging link between genomic instability and cancer-driven inflammation","authors":"Triet M. Bui,&nbsp;Ronen Sumagin","doi":"10.1016/j.mrfmmm.2022.111778","DOIUrl":"10.1016/j.mrfmmm.2022.111778","url":null,"abstract":"<div><p><span><span>Two recent studies by Bui and Butin-Israeli et al. have established the novel contribution of neutrophils to </span>genomic instability<span> induction and aberrant shaping of the DNA repair landscape, particularly observed in patients with inflammatory bowel diseases (IBD) and/or progressive </span></span>colorectal cancer<span><span> (CRC). In addition, these back-to-back studies uncovered a sharp increase in the numbers of micronuclei and lagging chromosomes in pre-cancerous and cancerous epithelium in response to prolonged PMN exposure. Given the emerging link between neutrophils and micronuclei as well as the established role of micronuclei in cGAS/STING activation, this special commentary aims to elaborate on the mechanisms by which CRC cells may adapt to neutrophil-driven genomic instability while concurrently sustain an inflamed tumor niche. We postulate that such tumor microenvironment with constant </span>immune cell presence, inflammatory milieu, and cumulative DNA damage can drive tumor adaptation and resistance to therapeutic interventions. Finally, we discuss potential novel therapeutic approaches that can be leveraged to target this emerging neutrophil-micronuclei pathological axis, thereby preventing perpetual CRC inflammation and unwanted tumor adaptation.</span></p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"824 ","pages":"Article 111778"},"PeriodicalIF":2.3,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10379545","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":"Characterization and implementation of a miniature X-ray system for live cell microscopy","authors":"Surendra Prajapati ,&nbsp;Maëlle Locatelli ,&nbsp;Caleb Sawyer ,&nbsp;Julia Holmes ,&nbsp;Keith Bonin ,&nbsp;Paul Black ,&nbsp;Pierre-Alexandre Vidi","doi":"10.1016/j.mrfmmm.2021.111772","DOIUrl":"10.1016/j.mrfmmm.2021.111772","url":null,"abstract":"<div><p>The study of radiation effects on biological tissues is a diverse field of research with direct applications to improve human health, in particular in the contexts of radiation therapy and space exploration. Understanding the DNA damage response following radiation exposure, which is a key determinant for mutagenesis, requires reproducible methods for delivering known doses of ionizing radiation (IR) in a controlled environment. Multiple IR sources, including research X-ray and gamma-ray irradiators are routinely used in basic and translational research with cell and animal models. These systems are however not ideal when a high temporal resolution is needed, for example to study early DNA damage responses with live cell microscopy. Here, we characterize the dose rate and beam properties of a commercial, miniature, affordable, and versatile X-ray source (Mini-X). We describe how to use Mini-X on the stage of a fluorescence microscope to deliver high IR dose rates (up to 29 Gy/min) or lower dose rates (≤ 0.1 Gy/min) in live cell imaging experiments. This article provides a blueprint for radiation biology applications with high temporal resolution, with a step-by-step guide to implement a miniature X-ray system on an imaging platform, and the information needed to characterize the system.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"824 ","pages":"Article 111772"},"PeriodicalIF":2.3,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39614416","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":"Aneuploidy, inflammation and diseases","authors":"Micheline Kirsch-Volders ,&nbsp;Michael Fenech","doi":"10.1016/j.mrfmmm.2022.111777","DOIUrl":"10.1016/j.mrfmmm.2022.111777","url":null,"abstract":"<div><p><span>This review discusses how numerical aneuploidy<span> may trigger inflammation in somatic cells and its consequences. Therefore we: i) summarized current knowledge on the cellular and molecular </span></span>pathological effects<span> of aneuploidy; ii) considered which of these aspects are able to trigger inflammation; iii) determined the genetic and environmental factors which may modulate the link between aneuploidy and inflammation; iv) explored the rôle of diet in prevention of aneuploidy and inflammation; v) examined whether aneuploidy and inflammation are causes and/or consequences of diseases; vi) identified the knowledge gaps and research needed to translate these observations into improved health care and disease prevention.</span></p><p>The relationships between aneuploidy, inflammation and diseases are complex, because they depend on which chromosomes are involved, the proportion of cells affected and which organs are aneuploid in the case of mosaic aneuploidy. Therefore, a systemic approach is recommended to understand the emergence of aneuploidy-driven diseases and to take preventive measures to protect individuals from exposure to aneugenic conditions.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"824 ","pages":"Article 111777"},"PeriodicalIF":2.3,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42155869","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":"Novel plasmids for the fluorescence-based evaluation of DNA mismatch repair in human cells","authors":"Arato Takedachi ,&nbsp;Erina Matsuishi ,&nbsp;Shouji Mizusaki ,&nbsp;Tomoki Nagasawa ,&nbsp;Ryosuke Fujikane ,&nbsp;Masumi Hidaka ,&nbsp;Shigenori Iwai ,&nbsp;Isao Kuraoka","doi":"10.1016/j.mrfmmm.2022.111779","DOIUrl":"10.1016/j.mrfmmm.2022.111779","url":null,"abstract":"<div><p><span><span>Mismatch repair<span> (MMR) is a highly conserved DNA repair pathway that corrects mismatched bases during DNA replication. The biological significance of MMR in human cells is underscored by the fact that dysfunction of the MMR pathway results in </span></span>Lynch syndrome<span>, which is associated with a genetic predisposition<span> to different cancer types. We have previously established a reporter mismatch plasmid to evaluate MMR using fluorescent proteins in living cells. However, the preparation of these plasmids requires significant amounts of time and money, which reduces their broad applicability. To overcome the abovementioned limitations, we produced in this study a novel reporter plasmid, pBSII NLS-MC-EGFP-tdTomato (pBET2), that can be used in the oligo swapping method. In this method, a nicking endonuclease produces a single-stranded DNA gap on a double-stranded DNA plasmid that can be replaced by ligation with synthetic </span></span></span>oligonucleotides<span><span>. It is significantly easier and more user-friendly than previous assays, which require in vitro DNA synthesis with single-stranded plasmid DNA and </span>purification<span><span> using ultracentrifugation<span> in cesium chloride-ethidium bromide gradients. The plasmid also contains a nicking site that allows the MMR repair machinery to efficiently distinguish the newly synthesized strand as a target for repair. In addition, a nuclear localization signal facilitates green fluorescent protein expression in the nucleus, which helps to verify the effectiveness of MMR using </span></span>fluorescence microscopy. Similar to the previous reporter plasmid, this construct facilitates the assessment of MMR proficiency in human living cells via the expression of fluorescent proteins while overcoming many of the negative aspects of the previous protocol.</span></span></p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"824 ","pages":"Article 111779"},"PeriodicalIF":2.3,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47791235","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 vitro and in silico analysis of a E559K mutation on cartilage oligomeric matrix protein","authors":"Jiahui Qiu ,&nbsp;Jichun Tan","doi":"10.1016/j.mrfmmm.2022.111774","DOIUrl":"10.1016/j.mrfmmm.2022.111774","url":null,"abstract":"<div><p><span><span>Pseudoachondroplasia (PSACH) is known as an autosomal dominant disorder associated with mutations in the gene of </span>cartilage oligomeric matrix protein<span> (COMP). The pathomolecular mechanisms of PSACH as a result of C-terminal globular region (CTD) mutations remain unclear. A heterozygous mutation (E559 K) in a Chinese family diagnosed with PSACH was reported in this study. To understand the pathogenesis of this mutation, we studied chondrogenic differentiation of patient menstrual blood-derived stem cells (MenSCs), and the impact of the mutation on structural changes of COMP was investigated using all-atom molecular dynamics simulation. The results suggested that the interactions with calcium and other molecules in the mutant structure were affected resulting in misfolding of the protein, which leads to ER stress and finally affects the survival of </span></span>chondrocytes. The findings may promote the understanding of the pathomolecular mechanisms of PSACH, and possibly the development of drugs to treat the disease.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"824 ","pages":"Article 111774"},"PeriodicalIF":2.3,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39859480","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":"Cell cycle involvement in cancer therapy; WEE1 kinase, a potential target as therapeutic strategy","authors":"Sajjad Vakili-Samiani ,&nbsp;Omid Joodi Khanghah ,&nbsp;Elham Gholipour ,&nbsp;Fatemeh Najafi ,&nbsp;Elham Zeinalzadeh ,&nbsp;Parisa Samadi ,&nbsp;Parisa Sarvarian ,&nbsp;Shiva Pourvahdani ,&nbsp;Shohre Karimi Kelaye ,&nbsp;Michael R. Hamblin ,&nbsp;Abbas Ali Hosseinpour Feizi","doi":"10.1016/j.mrfmmm.2022.111776","DOIUrl":"10.1016/j.mrfmmm.2022.111776","url":null,"abstract":"<div><p><span><span>Mitosis is the process of cell division and is regulated by checkpoints in the cell cycle. G1-S, S, and G2-M are the three main checkpoints that prevent initiation of the next phase of the cell cycle phase until previous phase has completed. DNA damage leads to activation of the G2-M checkpoint, which can trigger a downstream </span>DNA damage response<span> (DDR) pathway to induce cell cycle arrest while the damage is repaired. If the DNA damage cannot be repaired, the replication stress response (RSR) pathway finally leads to cell death by apoptosis, in this case called </span></span>mitotic catastrophe<span>. Many cancer treatments (chemotherapy and radiotherapy) cause DNA damages based on SSBs (single strand breaks) or DSBs (double strand breaks), which cause cell death through mitotic catastrophe. However, damaged cells can activate WEE1 kinase (as a part of the DDR and RSR pathways), which prevents apoptosis and cell death by inducing cell cycle arrest at G2 phase<span><span><span>. Therefore, inhibition of WEE1 kinase could sensitize cancer cells to chemotherapeutic drugs. This review focuses on the role of WEE1 kinase (as a biological macromolecule which has a molecular mass of 96 kDa) in the cell cycle, and its interactions with other regulatory pathways. In addition, we discuss the potential of WEE1 inhibition as a new therapeutic approach in the treatment of various cancers, such as </span>melanoma, breast cancer, </span>pancreatic cancer<span>, cervical cancer, etc.</span></span></span></p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"824 ","pages":"Article 111776"},"PeriodicalIF":2.3,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42087612","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 Kidney-Expressed Transcription Factor Zkscan3 is Dispensable for Autophagy Transcriptional Regulation and Aki Progression in Mouse","authors":"Huafeng Liu, Ze-jian Liu, Xiaoyu Li, Xingyu Li, Zixian Li, Huixia Chen, S-Q Gong, Minjie Zhang, Yaozhi Zhang, Zhihang Li, Lin Yang","doi":"10.2139/ssrn.4048743","DOIUrl":"https://doi.org/10.2139/ssrn.4048743","url":null,"abstract":"","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"1 1","pages":""},"PeriodicalIF":2.3,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68684025","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":"Distribution of copy number variations and rearrangement endpoints in human cancers with a review of literature","authors":"Golrokh Mirzaei ,&nbsp;Ruben C. Petreaca","doi":"10.1016/j.mrfmmm.2021.111773","DOIUrl":"10.1016/j.mrfmmm.2021.111773","url":null,"abstract":"<div><p>Copy number variations<span> (CNVs) which include deletions, duplications, inversions, translocations, and other forms of chromosomal re-arrangements are common to human cancers. In this report we investigated the pattern of these variations with the goal of understanding whether there exist specific cancer signatures. We used re-arrangement endpoint data deposited on the Catalogue of Somatic Mutations<span> in Cancers (COSMIC) for our analysis. Indeed, we find that human cancers are characterized by specific patterns of chromosome rearrangements endpoints which in turn result in cancer specific CNVs. A review of the literature reveals tissue specific mutations which either drive these CNVs or appear as a consequence of CNVs because they confer an advantage to the cancer cell. We also identify several rearrangement endpoints hotspots that were not previously reported. Our analysis suggests that in addition to local chromosomal architecture, CNVs are driven by the internal cellular or nuclear physiology of each cancer tissue.</span></span></p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"824 ","pages":"Article 111773"},"PeriodicalIF":2.3,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9755472","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":"Genome-wide profiles of UV lesion susceptibility, repair, and mutagenic potential in melanoma","authors":"Brian S. Perez,&nbsp;Ka Man Wong,&nbsp;Erin K. Schwartz ,&nbsp;Rafael E. Herrera,&nbsp;Devin A. King,&nbsp;Pablo E. García-Nieto,&nbsp;Ashby J. Morrison","doi":"10.1016/j.mrfmmm.2021.111758","DOIUrl":"10.1016/j.mrfmmm.2021.111758","url":null,"abstract":"<div><p>Exposure to the ultraviolet (UV) radiation in sunlight creates DNA lesions, which if left unrepaired can induce mutations and contribute to skin cancer. The two most common UV-induced DNA lesions are the <em>cis-syn</em> cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs), both of which can initiate mutations. Interestingly, mutation frequency across the genomes of many cancers is heterogenous with significant increases in heterochromatin. Corresponding increases in UV lesion susceptibility and decreases in repair are observed in heterochromatin versus euchromatin. However, the individual contributions of CPDs and 6-4PPs to mutagenesis have not been systematically examined in specific genomic and epigenomic contexts. In this study, we compared genome-wide maps of 6-4PP and CPD lesion abundances in primary cells and conducted comprehensive analyses to determine the genetic and epigenetic features associated with susceptibility. Overall, we found a high degree of similarity between 6-4PP and CPD formation, with an enrichment of both in heterochromatin regions. However, when examining the relative levels of the two UV lesions, we found that bivalent and Polycomb-repressed chromatin states were uniquely more susceptible to 6-4PPs. Interestingly, when comparing UV susceptibility and repair with melanoma mutation frequency in these regions, disparate patterns were observed in that susceptibility was not always inversely associated with repair and mutation frequency. Functional enrichment analysis hint at mechanisms of negative selection for these regions that are essential for cell viability, immune function and induce cell death when mutated. Ultimately, these results reveal both the similarities and differences between UV-induced lesions that contribute to melanoma.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"823 ","pages":"Article 111758"},"PeriodicalIF":2.3,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.mrfmmm.2021.111758","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39263477","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}