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

SIRT6 regulates the HIPK2/P53 pathway to reduce oxidative stress and apoptosis to attenuate vancomycin-induced nephrotoxicity

IF 1.5 4区医学

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2025-01-01 DOI: 10.1016/j.mrfmmm.2024.111897

Xiuying Feng , Yunhui Liu , Lei Su , Luyang Xu

{"title":"SIRT6 regulates the HIPK2/P53 pathway to reduce oxidative stress and apoptosis to attenuate vancomycin-induced nephrotoxicity","authors":"Xiuying Feng , Yunhui Liu , Lei Su , Luyang Xu","doi":"10.1016/j.mrfmmm.2024.111897","DOIUrl":"10.1016/j.mrfmmm.2024.111897","url":null,"abstract":"<div><div>SIRT6 is known to play a protective role in several kidney diseases; however, its role in vancomycin-induced renal injury remains unclear. This study aims to confirm the role and related mechanisms of SIRT6 in vancomycin-induced renal injury. To develop a kidney damage model, mice were given vancomycin injections for seven days. Additionally, an in vivo transfection with a SIRT6 overexpression plasmid was performed. PCR and Western blot analyses were used to assess the SIRT6 mRNA and protein expression levels in renal tissue. HE staining was performed to evaluate renal tissue damage, while Scr and BUN were measured using specialized kits. Renal tissue apoptotic cells were labeled using a TUNEL kit, and the levels of the antioxidant enzymes SOD and GSH were measured using appropriate kits. Western blot was used to identify HIPK2, p-p53, and p53 protein expression in the renal tissue. The results reveal that SIRT6 is expressed at markedly low levels in renal tissue. Furthermore, mice administered vancomycin exhibited a significant increase in Scr and BUN levels, indicating impaired renal function. Histological examination through HE staining demonstrated considerable damage to the renal tissue of the vancomycin group. Additionally, the renal tissue of the mice in the vancomycin group displayed reduced levels of the antioxidant enzymes SOD and GSH, an increased number of TUNEL-positive cells, and significantly elevated levels of HIPK2 and p-p53 protein expression. Moreover, the mice transfected with SIRT6 exhibited significant improvements in previously described symptoms. These findings imply that the inhibition of HIPK2/p53 by SIRT6 may represent a promising therapeutic strategy for alleviating vancomycin-induced nephrotoxicity.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"830 ","pages":"Article 111897"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143178151","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}

引用次数: 0

The complex development of psoralen-interstrand crosslink resistance in Escherichia coli requires AcrR inactivation, retention of a marbox sequence, and one of three MarA, SoxS, or Rob global regulators

IF 1.5 4区医学

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2025-01-01 DOI: 10.1016/j.mrfmmm.2025.111898

Travis K. Worley , Ayah H. Asal, Lo Cooper, Charmain T. Courcelle, Justin Courcelle

{"title":"The complex development of psoralen-interstrand crosslink resistance in Escherichia coli requires AcrR inactivation, retention of a marbox sequence, and one of three MarA, SoxS, or Rob global regulators","authors":"Travis K. Worley , Ayah H. Asal, Lo Cooper, Charmain T. Courcelle, Justin Courcelle","doi":"10.1016/j.mrfmmm.2025.111898","DOIUrl":"10.1016/j.mrfmmm.2025.111898","url":null,"abstract":"<div><div>Crosslinking agents, such as psoralen and UVA radiation, can be effectively used as antimicrobials and for treating several dysplastic conditions in humans, including some cancers. Yet, both cancer cells and bacteria can become resistant to these compounds, making it important to understand how resistance develops. Recently, several mutants were isolated that developed high levels of resistance to these compounds through upregulation of components of the AcrAB-TolC efflux pump. Here, we characterized these mutants and found that resistance specifically requires inactivating mutations of the <em>acrR</em> transcriptional repressor which also retain the <em>marbox</em> sequence found within this coding region. In addition, the presence of any one of three global regulators, MarA, SoxS, or Rob, is necessary and sufficient to bind to the <em>marbox</em> sequence and activate resistance. Notably, although psoralen is a substrate for the efflux pump, these regulators are not naturally responsive to this stress as neither psoralen, UVA, nor crosslink induction upregulates <em>acrAB</em> expression in the absence of mutation.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"830 ","pages":"Article 111898"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143178152","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}

引用次数: 0

Genomic and molecular landscape of gallbladder cancer elucidating pathogenic mechanisms novel therapeutic targets and clinical implications 胆囊癌的基因组和分子景观阐明致病机制、新治疗靶点和临床意义。

IF 1.5 4区医学

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2025-01-01 DOI: 10.1016/j.mrfmmm.2024.111896

Manishankar Kumar , Arun Kumar , Abhinav Srivastav , Ashok Ghosh , Dhruv Kumar

{"title":"Genomic and molecular landscape of gallbladder cancer elucidating pathogenic mechanisms novel therapeutic targets and clinical implications","authors":"Manishankar Kumar , Arun Kumar , Abhinav Srivastav , Ashok Ghosh , Dhruv Kumar","doi":"10.1016/j.mrfmmm.2024.111896","DOIUrl":"10.1016/j.mrfmmm.2024.111896","url":null,"abstract":"<div><div>Gallbladder cancer (GBC) is an aggressive malignancy with a poor prognosis, often diagnosed at advanced stages due to subtle early symptoms. Recent studies have provided a comprehensive view of GBC's genetic and mutational landscape, uncovering crucial pathways involved in its pathogenesis. Environmental exposures, particularly to heavy metals, have been linked to elevated GBC risk. Established signaling pathways, including hormonal, apoptotic, metabolic, inflammatory, and DNA damage repair pathways, are integral to GBC progression, and evidence points to the involvement of specific germline and somatic mutations in its development. Key mutations in genes such as KRAS, TP53, IDH1/2, ERBB, PIK3CA, MET, MYC, BRAF, MGMT, CDKN2A and p16 have been identified as contributors to tumorigenesis, with additional alterations including chromosomal aberrations and epigenetic modifications. These molecular insights reveal several potential therapeutic targets that could address the limited treatment options for GBC. Promising therapeutic avenues under investigation include immune checkpoint inhibitors, tyrosine kinase inhibitors, tumor necrosis factor-related apoptosis-inducing ligands (TRAIL), and phytochemicals. Numerous clinical trials are assessing the efficacy of these targeted therapies. This review provides a detailed examination of GBC's genetic and mutational underpinnings, highlighting critical pathways and emerging therapeutic strategies. We discuss the implications of germline and somatic mutations for early detection and individualized treatment, aiming to bridge current knowledge gaps. By advancing our understanding of GBC's molecular profile, we hope to enhance diagnostic accuracy and improve treatment outcomes, ultimately paving the way for precision medicine approaches in managing GBC.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"830 ","pages":"Article 111896"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928669","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}

引用次数: 0

Evaluation of the simultaneous effects of KRAS G12V and LCS6 alterations on the behavior of head and neck squamous cell carcinoma 评估 KRAS G12V 和 LCS6 改变同时对头颈部鳞状细胞癌行为的影响。

IF 1.5 4区医学

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2025-01-01 DOI: 10.1016/j.mrfmmm.2024.111895

Vildan Betul Yenigun , Vasfiye Betul Ucar , Zeynep Betul Sari , Ali Ahmed Azzawri , Yasemin Sena Acar , Muhammed Burak Kaplan , Suleyman Nergiz , Hasan Acar

{"title":"Evaluation of the simultaneous effects of KRAS G12V and LCS6 alterations on the behavior of head and neck squamous cell carcinoma","authors":"Vildan Betul Yenigun , Vasfiye Betul Ucar , Zeynep Betul Sari , Ali Ahmed Azzawri , Yasemin Sena Acar , Muhammed Burak Kaplan , Suleyman Nergiz , Hasan Acar","doi":"10.1016/j.mrfmmm.2024.111895","DOIUrl":"10.1016/j.mrfmmm.2024.111895","url":null,"abstract":"<div><h3>Background</h3><div>Head and neck squamous cell carcinomas are the seventh most common cancer accounting for 90 % of malignant neoplasia of the upper respiratory system. <em>KRAS</em> is a very important oncogene, leading to the suppression of apoptosis, and promoting the pathogenesis and development of tumors. MicroRNAs (miRNAs) are highly conserved, small noncoding RNA molecules aberrantly expressed in various pathologies including regulation of tumor and metastasis-associated genes. Variant (rs61764370) of the let-7 miRNA complementary site of <em>KRAS</em> 3’-untranslated region (KRAS-LCS6) has been shown to disrupt the ability of miRNAs to target genes resulting in differential target mRNA and protein expression.</div></div><div><h3>Methods</h3><div>In this study, the effects of variant complementary site LCS6 of the let-7 miRNA in head and neck cancer were investigated <em>in vitro</em> using laryngeal carcinoma HEp-2 carrying G12V and LCS6 alterations in the <em>KRAS</em> gene. Non-cancer HEK-293 cells were also used as control cells.</div></div><div><h3>Results</h3><div>G12V mutation in the <em>KRAS</em> gene increases invasion capacity and is specifically active on the ERK pathway associated with metastasis. Alteration in the LCS6 region of the <em>KRAS</em> gene did not show additional effects compared to cells only carrying G12V mutation. Our results also showed that the coexistence of G12V and LCS6 alterations is lethal to specific cell types, UM-SCC-17A laryngeal cancer cells in our case.</div></div><div><h3>Conclusions</h3><div>The LCS6 region alteration of the <em>KRAS</em> may play a key role in further cancer progression, and more research is needed to fully understand the mechanisms by which the LCS6 alterations promote cancer progression.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"830 ","pages":"Article 111895"},"PeriodicalIF":1.5,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819981","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}

引用次数: 0

High expression of SLC34A2 contributes to chemoresistance of non-small cell lung cancer against gefitinib: The critical role of miR-124–3p SLC34A2的高表达导致了非小细胞肺癌对吉非替尼的化疗耐药性：miR-124-3p 的关键作用。

IF 1.5 4区医学

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2024-11-19 DOI: 10.1016/j.mrfmmm.2024.111894

Chao Tan , Li Zhang , Sai Chen , Zhenzhen Tian , Nina Zhou , Yuling Li , Qi Wang , Lu Chen

{"title":"High expression of SLC34A2 contributes to chemoresistance of non-small cell lung cancer against gefitinib: The critical role of miR-124–3p","authors":"Chao Tan , Li Zhang , Sai Chen , Zhenzhen Tian , Nina Zhou , Yuling Li , Qi Wang , Lu Chen","doi":"10.1016/j.mrfmmm.2024.111894","DOIUrl":"10.1016/j.mrfmmm.2024.111894","url":null,"abstract":"<div><div>Gefitinib is a therapeutic agent used to treat lung carcinoma, including non-small cell lung cancer (NSCLC). However, mechanisms underlying NSCLC cell resistance to gefitinib remain largely uncharacterized. In this study, we explored the association between the miR-124–3p/SLC34A2 axis and gefitinib resistance using a series of <em>in vivo</em> and <em>in vitro</em> assays. Data indicated that miR-124–3p is downregulated, while SLC34A2 is upregulated, in gefitinib-resistant NSCLC cells. Overexpression of miR-124–3p reduced NSCLC cell resistance to gefitinib by suppressing cell viability, inducing apoptosis, and decreasing N-cadherin expression. Conversely, inhibiting miR-124–3p in NSCLC cells led to increased cell viability and reduced apoptosis. Overexpression of SLC34A2 in NSCLC cells further heightened gefitinib resistance. In a xenograft mouse model, SLC34A2 overexpression promoted solid tumor growth and metastasis, while miR-124–3p overexpression inhibited these effects. Our results highlight that the interaction between miR-124–3p and SLC34A2 plays an indispensable role in determining gefitinib resistance in NSCLC cells.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"830 ","pages":"Article 111894"},"PeriodicalIF":1.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142696286","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}

引用次数: 0

The mutagenic properties of formaldehyde and acetaldehyde: Reflections on half a century of progress 甲醛和乙醛的诱变特性：对半个世纪进展的思考。

IF 1.5 4区医学

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2024-11-08 DOI: 10.1016/j.mrfmmm.2024.111886

Mahanish Jung Thapa, Kin Chan

引用次数: 0

ATM and ATR gene editing mediated by CRISPR/Cas9 in Chinese Hamster cells CRISPR/Cas9 在中国仓鼠细胞中介导的 ATM 和 ATR 基因编辑

IF 1.5 4区医学

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2024-07-01 DOI: 10.1016/j.mrfmmm.2024.111871

Junko Maeda, Piyawan Chailapakul, Takamitsu A. Kato

{"title":"ATM and ATR gene editing mediated by CRISPR/Cas9 in Chinese Hamster cells","authors":"Junko Maeda, Piyawan Chailapakul, Takamitsu A. Kato","doi":"10.1016/j.mrfmmm.2024.111871","DOIUrl":"10.1016/j.mrfmmm.2024.111871","url":null,"abstract":"<div><p>Chinese hamster-derived cell lines including Chinese hamster lung fibroblasts (V79) have been used as model somatic cell lines in radiation biology and toxicology research for decades and have been instrumental in advancing our understanding of DNA damage response (DDR) mechanisms. Whereas many mutant lines deficient in DDR genes have been generated more than over decades, several key DDR genes such as ATM and ATR have not been established in the Chinese hamster system. Here, we transfected CRISPR/Cas9 vectors targeting Chinese hamster ATM or ATR into V79 cells and investigated whether the isolated clones had the characteristics reported in human and mouse studies. We obtained two clones of ATM knockout cells containing an insertion or deletions in the targeted locus. The ATM knockouts with no detectable ATM protein expression exhibited increased sensitivity to radiation and DNA double strand break inducing agents, cell cycle checkpoint defects and defective chromatid break repair. These are all characteristics of defective ATM function. Among the obtained ATR cells, which contained mutations in both ATR alleles while maintaining normal levels of ATR protein expression, one clone exhibited hypersensitivity to UV and replication stress agents. In the present study, we successfully established CRISPR-Cas9 derived ATM knockout cells. We couldn't knock out the ATR gene but obtained ATR mutant cells. Our results showed that Chinese hamster origin ATM knockout cells and ATR mutant cells could be useful tools for further research to reveal oncogenic functions and effects of developing anti-cancer therapeutics.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"829 ","pages":"Article 111871"},"PeriodicalIF":1.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141638930","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}

引用次数: 0

Understanding the nucleotide composition and patterns of codon usage in the expression of human oral cancer genes 了解人类口腔癌基因表达中的核苷酸组成和密码子使用模式

IF 1.5 4区医学

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2024-07-01 DOI: 10.1016/j.mrfmmm.2024.111880

Tarikul Huda Mazumder , Arif Uddin

{"title":"Understanding the nucleotide composition and patterns of codon usage in the expression of human oral cancer genes","authors":"Tarikul Huda Mazumder , Arif Uddin","doi":"10.1016/j.mrfmmm.2024.111880","DOIUrl":"10.1016/j.mrfmmm.2024.111880","url":null,"abstract":"<div><p>Oral squamous cell carcinoma (OSCC) is primarily known as oral cancer (OC) that mostly occurs in mouth, lips and tongue. Mutations in some of the genes cause OC and some genes are risk factors for progression of OC. In this study, we analyzed the compositional features and pattern of codon usage in genes involved in OC using computational method as no work was reported yet. Compositional features suggested that the overall GC content was higher <em>i.e.</em> genes were GC rich. Effective number of codons (ENC) values ranged from 34.6 to 55.9 with a mean value of 49.03±4.22 representing low codon usage bias (CUB). Correspondence analysis (COA) suggested that the codon usage pattern was different in different genes. In genes associated with OC, highly significant correlation was observed between GC12 and GC3 (r=0.454, p<0.01) suggesting that directional mutation affected all the three codon positions. This is the first report on pattern of codon usage pattern on genes involved in OC, which not only alludes a new perspective for elucidating the mechanisms of biased usage of synonymous codons but also provide valuable clues for molecular genetic engineering.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"829 ","pages":"Article 111880"},"PeriodicalIF":1.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142084355","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}

引用次数: 0

Agrimonolide inhibits glycolysis in ovarian cancer cells by regulating HIF1A 嘧菌酯通过调节 HIF1A 抑制卵巢癌细胞中的糖酵解作用

IF 1.5 4区医学

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2024-07-01 DOI: 10.1016/j.mrfmmm.2024.111884

Yi Yang, Huimin Wang, Qiong Wei, Chun Li

{"title":"Agrimonolide inhibits glycolysis in ovarian cancer cells by regulating HIF1A","authors":"Yi Yang, Huimin Wang, Qiong Wei, Chun Li","doi":"10.1016/j.mrfmmm.2024.111884","DOIUrl":"10.1016/j.mrfmmm.2024.111884","url":null,"abstract":"<div><h3>Background</h3><div>Ovarian cancer is one of the most common tumors affecting females, significantly disrupting their quality of life. Agrimonolide, an extract derived from Agrimony (<em>Agrimonia pilosa</em> Ledeb.), has been shown to exert various regulatory effects on several diseases. Notably, recent studies indicate that Agrimonolide may attenuate the progression of ovarian cancer. However, the detailed regulatory mechanisms of Agrimonolide in this context require further investigation.</div></div><div><h3>Purpose</h3><div>To determine the significance of HIF1A as a key target in ovarian cancer and its potential underlying signaling pathway.</div></div><div><h3>Methods</h3><div>Cell viability and proliferation were assessed using CCK-8 and colony formation assays. Glucose uptake and lactate production were measured using commercial kits, and the extracellular acidification rate (ECAR) was evaluated. Protein expression levels were analyzed through western blotting.</div></div><div><h3>Results</h3><div>Our network pharmacology analysis identified HIF1A as a crucial target and signaling pathway in ovarian cancer. Furthermore, treatment with Agrimonolide (20 μM and 40 μM) inhibited the growth of ovarian cancer cells. Agrimonolide also reduced glycolytic activity in these cells. Additionally, Agrimonolide treatment led to decreased expression levels of HIF1A, HK2, and LDHA in ovarian cancer cells. Rescue assays revealed that glucose uptake and lactate production were diminished following Agrimonolide treatment; however, these effects were reversed upon overexpression of HIF1A.</div></div><div><h3>Conclusion</h3><div>This study showed that Agrimonolide can suppress glycolysis in ovarian cancer cells by modulating HIF1A, supporting Agrimonolide as a promising therapeutic agent for ovarian cancer treatment.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"829 ","pages":"Article 111884"},"PeriodicalIF":1.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142357959","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}

引用次数: 0

ALDH2 mutations and defense against genotoxic aldehydes in cancer and inherited bone marrow failure syndromes 癌症和遗传性骨髓衰竭综合征中的 ALDH2 基因突变和对基因毒性醛的防御。

IF 1.5 4区医学

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2024-07-01 DOI: 10.1016/j.mrfmmm.2024.111870

Anthony Yiu-Ho Woo, Lina Jia

{"title":"ALDH2 mutations and defense against genotoxic aldehydes in cancer and inherited bone marrow failure syndromes","authors":"Anthony Yiu-Ho Woo, Lina Jia","doi":"10.1016/j.mrfmmm.2024.111870","DOIUrl":"10.1016/j.mrfmmm.2024.111870","url":null,"abstract":"<div><p>Reactive aldehydes, for instance, formaldehyde and acetaldehyde, are important endogenous or environmental mutagens by virtue of their abilities to produce a DNA lesion called interstrand crosslink (ICL). Aldehyde-metabolizing enzymes such as aldehyde dehydrogenases (ALDHs) and the Fanconi anemia (FA) pathway constitute the main defense lines against aldehyde-induced genotoxicity. Biallelic mutations of genes in any one of the FA complementation groups can impair the ICL repair mechanism and cause FA, a heterogeneous disorder manifested by bone marrow failure (BMF), congenital abnormality and a strong predisposition to cancer. The defective <em>ALDH2</em> polymorphism rs671 (<em>ALDH2*2</em>) is a known risk and prognostic factor for alcohol drinking-associated cancers. Recent studies suggest that it also promotes BMF and cancer development in FA, and its combination with alcohol dehydrogenase 5 (ADH5) mutations causes aldehyde degradation deficiency syndrome (ADDS), also known by its symptoms as aplastic anemia, mental retardation, and dwarfism syndrome. <em>ALDH2*2</em> and another pathogenic variant in the alcohol-metabolizing pathway, <em>ADH1B1*1</em>, is prevalent among East Asians. Also, other <em>ALDH2</em> genotypes with disease-modifying potentials have lately been identified in different populations. Therefore, it would be appropriate to summarize current knowledge of genotoxic aldehydes and defense mechanisms against them to shed new light on the pathogenic effects of <em>ALDH2</em> variants together with other genetic and environmental modifiers on cancer and inherited BMF syndromes. Lastly, we also presented potential treatment strategies for FA, ADDS and cancer based on the manipulation of aldehyde-induced genotoxicity.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"829 ","pages":"Article 111870"},"PeriodicalIF":1.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474098","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}

引用次数: 0