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

{"title":"DNA double-strand breaks induced by DNA topoisomerase IIα and reactive oxygen species lead to the integration of foreign DNA into the host genome","authors":"Aya Kurosawa ,&nbsp;Masumi Umehara ,&nbsp;Noritaka Adachi","doi":"10.1016/j.mrfmmm.2025.111924","DOIUrl":"10.1016/j.mrfmmm.2025.111924","url":null,"abstract":"<div><div>Foreign DNA integrates into the genome at low frequencies and random positions upon introduction into cells. This phenomenon, known as random integration, occurs when DNA double-strand breaks (DSBs) are repaired by non-homologous end-joining or polymerase theta-mediated end-joining, incorporating the foreign DNA into the genome. However, the mechanism underlying DSB generation in random integration remains unclear. In this study, we investigated the role of DNA topoisomerase II (Top2) and reactive oxygen species (ROS) in generating DSBs and examined their effects on random integration frequency. In Nalm-6 cells, the frequency of random integration increased following treatment with the Top2 inhibitor etoposide and hydrogen peroxide. Conversely, depletion of Top2α and cultivation under hypoxic conditions independently reduced the frequency of random integration, with their combination resulting in an even greater reduction. In gene targeting experiments at the <em>HPRT</em> locus, both Top2α depletion and hypoxic culture similarly reduced random integration. This suggests that DSBs generated by Top2α and ROS contribute to random integration and impede efficient gene targeting.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"832 ","pages":"Article 111924"},"PeriodicalIF":1.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145697779","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":"METTL3 promotes prostate cancer cell metastasis and EMT by mediating NUP210 m6A modification","authors":"Shaoxing Wang,&nbsp;Jinming Li,&nbsp;Jun Jiang,&nbsp;Jiahao Liu,&nbsp;Shusen Zuo","doi":"10.1016/j.mrfmmm.2026.111930","DOIUrl":"10.1016/j.mrfmmm.2026.111930","url":null,"abstract":"<div><h3>Background</h3><div>Prostate cancer (PCa) is an age-related epithelial malignancy with high metastatic potential. Although nucleoporin 210 (NUP210) is implicated in tumor progression, its role and mechanism in PCa metastasis remain unexplored.</div></div><div><h3>Methods</h3><div>Bioinformatics analysis (Gene Expression Omnibus (GEO)/The University of Alabama at Birmingham CANcer data analysis Portal (UALCAN) databases) and experimental validation (quantitative real-time PCR (qRT-PCR) and western blot) were applied to assess the expression of NUP210, methyltransferase-like 3 (METTL3), metastasis-related markers, and epithelial-mesenchymal transition (EMT)-related markers. Functional assays (transwell, <em>in vivo</em> metastasis models) and mechanistic studies (methylated RNA immunoprecipitation (MeRIP), RNA binding protein immunoprecipitation (RIP), and mRNA stability assays) were performed to elucidate the METTL3/NUP210 axis.</div></div><div><h3>Results</h3><div>NUP210 and METTL3 were highly expressed in PCa tissues and cells. Knockdown of NUP210 significantly inhibited PCa metastasis and EMT. Also, the animal study revealed that NUP210 silencing could inhibit the lung metastasis of PCa <em>in vivo</em>. METTL3-mediated N6-methyladenosine (m6A) modification stabilized NUP210 mRNA, and rescue experiments confirmed that NUP210 overexpression reversed the inhibitory effects of METTL3 silencing on PCa cell metastasis and EMT.</div></div><div><h3>Conclusion</h3><div>The METTL3-mediated m6A modification of NUP210 may promote PCa metastasis and EMT. This newly identified METTL3/NUP210 axis deepens the understanding of PCa progression and suggests its potential for further therapeutic exploration.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"832 ","pages":"Article 111930"},"PeriodicalIF":1.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147349759","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":"Effect of p53 gene mutation with loss of function on the expression of genes and proteins involved in cell proliferation","authors":"Gyeong Hee Kim ,&nbsp;Moon-Moo Kim","doi":"10.1016/j.mrfmmm.2026.111931","DOIUrl":"10.1016/j.mrfmmm.2026.111931","url":null,"abstract":"<div><div>The tumor suppressor gene TP53 plays a vital role in preserving genomic integrity by regulating cell cycle progression, DNA repair mechanisms, and apoptosis. This study aims to examine how CRISPR/Cas9-induced loss-of-function mutations in the p53 gene influence cellular processes on cell cycle regulation and tumorigenic signaling in HT1080 human fibrosarcoma cells. Successful TP53 gene disruption was confirmed by Sanger sequencing, and its structural modelling using AlphaFold2 and ChimeraX confirmed alterations in the predicted TP53 protein structure compared to that of wild type. Gene expression analyses, conducted via RT-PCR and qPCR, demonstrated a marked decrease in TP53 mRNA expression within the modified cells. Despite the mutation, the edited cells elevated activity of the senescence marker β-galactosidase (SA-β-gal). They decreased the production of collagen, suggesting that the structural disruption caused by CRISPR/Cas9 leads to the loss of functional p53 activity. Western blotting and immunofluorescence assays further revealed a remarkable downregulation of key cell cycle and tumorigenesis-related proteins, including TP53, phosphorylated TP53 (p-TP53), acetylated TP53 (ac-TP53), MMP-2, cyclin D, cyclin E, AKT, BAX, MDM2, and phosphorylated Rb (p-Rb) in the edited cells relative to the wild-type counterpart. Our results suggest that the TP53 mutation may disrupt essential pathways related to cell proliferation and stress responses. This provides new insights into TP53 functionality and underscores its potential as a therapeutic target in cancer biology.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"832 ","pages":"Article 111931"},"PeriodicalIF":1.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147286871","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 of pathogenic missense mutations in nuclear encoded mitochondrial dynamin −1 like protein","authors":"Kaniha Sivakumar,&nbsp;Nihala Sidhic,&nbsp;Usha Subbiah,&nbsp;Sudhan Mookkandi","doi":"10.1016/j.mrfmmm.2026.111928","DOIUrl":"10.1016/j.mrfmmm.2026.111928","url":null,"abstract":"<div><h3>Background</h3><div>The <em>DNM1L</em> gene encodes the dynamin-related protein, Drp1, essential for mitochondrial fission. Impaired mitochondrial division contributes to cardiovascular, neurodegenerative, and metabolic disorders. This study aimed to identify and analyse deleterious nonsynonymous single nucleotide polymorphisms (nsSNPs) in <em>DNM1L</em> that may impair protein function.</div></div><div><h3>Methods</h3><div>An integrated in silico strategy combining multiple predictive tools (SIFT, PolyPhen-2, PhD-SNP, PANTHER, Meta-SNP, FATHMM, I-Mutant 2.0, INPS-MD, Medusa, MutPred2, DynaMut2, ConSurf, NetSurfP-2.0, STRING, GeneMANIA) was used to identify deleterious nonsynonymous SNPs (nsSNPs) in <em>DNM1L</em> and evaluate their structural and functional effects.</div></div><div><h3>Results</h3><div>Eleven nsSNPs (A395D, V417G, R60W, etc.) were consistently predicted to be pathogenic. These variants occurred at conserved residues and induced significant changes in protein stability, flexibility, and interaction potential. Functional annotations suggested possible alterations in metal binding, secondary structure, and post-translational modifications.</div></div><div><h3>Conclusion</h3><div>The identified <em>DNM1L</em> variants may compromise Drp1 function and contribute to mitochondrial dysfunction underlying disease mechanisms. This study provides a computational basis for future experimental validation and clinical exploration of <em>DNM1L</em>-associated disorders. These variants may underlie mitochondrial dysfunction contributing to neurodegenerative and metabolic disorders.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"832 ","pages":"Article 111928"},"PeriodicalIF":1.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147367842","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":"Targeting overexpressed oncogenes in esophageal cancer through miRNA-mediated gene silencing: Insights from binding affinity and thermodynamic profiling","authors":"Sabnam Nasrin Choudhury ,&nbsp;Tarikul Huda Mazumder ,&nbsp;Sahidul Saikia ,&nbsp;Arif Uddin","doi":"10.1016/j.mrfmmm.2026.111936","DOIUrl":"10.1016/j.mrfmmm.2026.111936","url":null,"abstract":"<div><div>Esophageal cancer (ESCA) ranks among the most lethal malignancies worldwide, with late-stage diagnosis, poor prognosis, and limited treatment options contributing to its high mortality. MicroRNAs (miRNAs), short non-coding RNAs with gene-silencing functions, have emerged as crucial regulators in cancer biology and hold promise as diagnostic and therapeutic tools. This study investigates miRNA–mRNA interactions in ESCA using a comprehensive in silico approach to uncover potential regulatory nodes that may underlie tumor progression. Fourteen overexpressed genes in both esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) were selected. TargetScanHuman and miRDB were used to detect miRNAs with high-confidence 8mer seed matches (score ≥90). The majority of genes exhibited multi-miRNA targeting with clustered or overlapping seed regions, indicative of cooperative or redundant repression mechanisms. Several miRNAs demonstrated highly stable interactions, with favorable MFE and ΔG values, reinforcing their silencing potential. GC/GC3 enrichment further supported duplex stability. GO analysis revealed that the target genes are predominantly involved in transcriptional regulation, apoptosis inhibition, immune response modulation, and cell signaling-pathways central to cancer pathogenesis. TCGA-based validation showed that only a subset of predicted interactions is functionally relevant, with hsa-miR-30d-5p exhibiting a significant inverse correlation with CHST2. These findings highlight the importance of integrating predictive and expression data to identify biologically meaningful miRNA-mRNA interactions in esophageal cancer.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"832 ","pages":"Article 111936"},"PeriodicalIF":1.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147848254","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":"SPDEF-mediated BIRC5 transcriptional activation enhances non-small cell lung cancer progression","authors":"Zhixiong Qiao ,&nbsp;Zhiping Lv ,&nbsp;Xuyang Song,&nbsp;Jinxi He","doi":"10.1016/j.mrfmmm.2025.111926","DOIUrl":"10.1016/j.mrfmmm.2025.111926","url":null,"abstract":"<div><h3>Background</h3><div>SAM-pointed domain-containing ETS transcription factor (SPDEF), an ETS family transcription factor (TF), functions as a tumor-promoting factor in non-small cell lung cancer (NSCLC). However, the precise mechanisms of SPDEF in regulating NSCLC pathogenesis remain to be fully characterized.</div></div><div><h3>Methods</h3><div>Bioinformatics analyses were used to identify disease-associated TFs and downstream targets. A protein-protein interaction (PPI) network was constructed to predict hub TFs. The relationship between SPDEF and BIRC5 was validated by luciferase and ChIP assays. The influences on cell phenotypes were evaluated by testing cell colony formation, invasion, migration, and apoptosis. Xenograft studies were used to explore the role in tumor growth.</div></div><div><h3>Results</h3><div>This study revealed 101 disease-associated TFs in NSCLC. GO enrichment analysis of these TFs demonstrated significant enrichment in biological processes including lung development, lung differentiation, and Wnt signaling pathway. PPI analysis revealed FOXA1, GATA6, TBX2, and SPDEF as core regulatory factors. SPDEF and BIRC5 levels were upregulated in NSCLC tumors and cell lines. Mechanistically, SPDEF induced BIRC5 upregulation through transcriptional regulation. SPDEF depletion impaired NSCLC cell invasion, migration, and clonogenicity while inducing apoptosis <em>in vitro</em>, which could be abolished by BIRC5 reconstitution. Moreover, SPDEF deficiency inhibited A549 tumor growth in subcutaneous xenograft models. Additionally, BIRC5 activated the Wnt/β-catenin pathway in NSCLC cells.</div></div><div><h3>Conclusion</h3><div>Our findings demonstrate the tumor-promoting function of SPDEF in NSCLC by transcriptionally activating BIRC5, highlighting SPDEF as a candidate target for future NSCLC-directed therapies.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"832 ","pages":"Article 111926"},"PeriodicalIF":1.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145798323","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 oncogenic role of U2AF2/HKDC1 cascade in colorectal cancer by promoting cancer cell glycolysis and malignant phenotypes","authors":"Wenjuan Feng ,&nbsp;Mingfeng Wu ,&nbsp;Hanyang Zou ,&nbsp;Yanpu Chen","doi":"10.1016/j.mrfmmm.2026.111929","DOIUrl":"10.1016/j.mrfmmm.2026.111929","url":null,"abstract":"<div><h3>Background</h3><div>Dysregulation of hexokinase domain component 1 (HKDC1), a central regulator of glucose metabolism, plays a pathogenic role in colorectal cancer (CRC). The current research investigated the RNA-binding protein (RBP)-mediated mechanism in driving HKDC1 dysregulation in CRC.</div></div><div><h3>Methods</h3><div>Expression of mRNAs was detected by quantitative PCR, and protein expression analysis was performed by immunoblot and immunohistochemical assays. Cell invasiveness, migration, apoptosis, colony formation and proliferation were evaluated by transwell, wound healing, TUNEL staining, colony formation, and CCK-8 assays, respectively. Glucose consumption and lactate production were quantified to examine glycolysis. Luciferase, RNA immunoprecipitation (RIP) and mRNA stability assays were used to confirm the U2AF2/HKDC1 relationship. Xenograft models were established to examine the <em>in vivo</em> function.</div></div><div><h3>Results</h3><div>In human CRC, HKDC1 and U2AF2 were present at higher levels, and HKDC1 expression was positively associated with U2AF2 level. Cells with HKDC1 depletion presented repressed growth, enhanced apoptosis, reduced migratory capacity, as well as suppressive invasiveness and glycolysis. Mechanistically, U2AF2 stabilized HKDC1 mRNA and induced HKDC1 protein upregulation. Depletion of U2AF2 decreased cell growth, migratory capacity, invasiveness, and glycolysis and promoted apoptosis <em>in vitro</em>, as well as diminished the <em>in vivo</em> tumorigenicity of HCT116 cells, which could be partially abolished by HKDC1 increase.</div></div><div><h3>Conclusion</h3><div>Our observations demonstrate that U2AF2 works as an mRNA-stabilizing factor for HKDC1, and the U2AF2/HKDC1 axis contributes to CRC glycolysis and development. Targeting the novel axis might form the basis of a promising therapy for CRC treatment.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"832 ","pages":"Article 111929"},"PeriodicalIF":1.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146168584","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 Taq polymerase induced mutations in part of BRAF exon 15 by sequencing and mutation enrichment","authors":"Per O. Ekstrøm ,&nbsp;Sigve Nakken ,&nbsp;Eivind Hovig","doi":"10.1016/j.mrfmmm.2026.111934","DOIUrl":"10.1016/j.mrfmmm.2026.111934","url":null,"abstract":"<div><div>The polymerase chain reaction (PCR) is a fundamental technique in molecular biology, enabling the amplification of specific DNA sequences for various applications. Despite its utility, the fidelity of DNA polymerases used during amplification is not perfect, leading to the introduction of replication errors such as base substitutions, insertions, and deletions into the amplified products. These errors can significantly impact downstream analyses, where correct identification of true biological DNA variations is crucial.</div><div>This study aimed to investigate the error rates of Taq polymerase during PCR amplification of a 127 base pair sequence surrounding codon 600 of the BRAF gene. This region, located in exon 15, is of significant clinical interest due to its association with various cancers. Using the MiSeq platform in combination with a constant denaturant capillary electrophoresis (CDCE) assay, we analyzed the errors introduced by Taq polymerase. On average, 1.1 million sequencing reads were generated for each PCR-amplified sample, in combination with mutant enrichment through CDCE to allow for the observation of mutations from the background noise.</div><div>We identified a non-random mutational spectrum with respect to positions, with several hotspots. The majority of mutational changes were transitions, either A to G or T to C. Noteworthy is the mutation in codon 600, where the second base “T” is mutated to an “A,” corresponding to the clinically relevant V600E mutation.</div><div>This study highlights the importance of understanding polymerase-induced errors in PCR and their implications for NGS data accuracy. The enrichment strategy employed here demonstrates a method for detecting and analyzing these errors, providing valuable insights for genomic research and clinical applications.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"832 ","pages":"Article 111934"},"PeriodicalIF":1.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147577237","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":"Role of c-Myc-regulated miR-196a-5p in the progression of triple-negative breast cancer: Potential involvement of HOXA7 and HOXB7","authors":"Xin-Yu Song ,&nbsp;Le Yang ,&nbsp;Hui-Ling Li ,&nbsp;Hao-Yi Xu ,&nbsp;Xiao-Li Xu ,&nbsp;Kang Yan ,&nbsp;Yuan-Jing Liu ,&nbsp;Zuliyaer Mierzhakenmu ,&nbsp;Rui Xu ,&nbsp;Chao Dong","doi":"10.1016/j.mrfmmm.2025.111923","DOIUrl":"10.1016/j.mrfmmm.2025.111923","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to elucidate the regulatory role of c-Myc-associated miR-196a-5p in the progression of triple-negative breast cancer (TNBC). We further explored its target genes to investigate possible mechanisms of action.</div></div><div><h3>Methods</h3><div>High-throughput sequencing was employed to profile microRNA expression in MDA-MB-231 cells with differential c-Myc expression. Differentially expressed microRNAs were identified, and miR-196a-5p levels, along with the expression of predicted target genes, were quantified using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in c-Myc knockdown cells. Candidate targets were predicted using miRDB and TargetScan databases and further validated by qRT-PCR and Western blotting in MDA-MB-231 and MDA-MB-468 cells with modulated miR-196a-5p expression. Functional assays, including clonogenic assays, flow cytometry, and Transwell migration and invasion assays were conducted to evaluate the effects of miR-196a-5p on cellular behavior.</div></div><div><h3>Results</h3><div>miR-196a-5p expression was significantly reduced in c-Myc-deficient cells and exhibited a positive association with c-Myc levels. Bioinformatic analysis identified HOXA7 and HOXB7 as miR-196a-5p putative targets, with inverse expression patterns observed between the microRNA and these genes. Downregulation of miR-196a-5p resulted in elevated expression of HOXA7 and HOXB7, whereas its overexpression resulted in their suppression. Functionally, increased levels of miR-196a-5p were associated with enhanced proliferation, invasion, and migration, along with decreased apoptosis in TNBC cells.</div></div><div><h3>Conclusion</h3><div>Our findings reveal a positive correlation between c-Myc and miR-196a-5p in TNBC, suggesting that miR-196a-5p may promote tumor progression by regulating cellular proliferation, invasion, migration, and apoptosis. The inverse expression patterns between miR-196a-5p and HOXA7/HOXB7 imply these genes may be downstream targets, though direct causal relationships and detailed molecular mechanisms require further validation.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"832 ","pages":"Article 111923"},"PeriodicalIF":1.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738425","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":"Computational analysis of functional, structural and pathogenic impacts of missense SNPs in the human SOCS3 gene","authors":"Raviteja Reddy Alipeddi,&nbsp;Durga Neeharika Rani,&nbsp;Pallavi Sampanmudumby,&nbsp;Surekha Rani Hanumanth","doi":"10.1016/j.mrfmmm.2025.111925","DOIUrl":"10.1016/j.mrfmmm.2025.111925","url":null,"abstract":"<div><div>The Suppressor of Cytokine Signaling 3 (SOCS3) protein is a crucial negative regulator of cytokine-mediated signaling pathways, and genetic variations in <em>SOCS3</em> have been implicated in the development of multiple multi-factorial diseases (MFDs). In this study, a comprehensive <em>insilico</em> analysis was performed to evaluate the functional and structural consequences of eight missense single nucleotide polymorphisms (SNPs) (rs37610117, rs111889212, rs1061489, rs376015024, rs17849241, rs201763454, rs200504273, rs150709546) retrieved from the NCBI dbSNP database. Functional predictions using SIFT, PolyPhen-2, PhD-SNP, PANTHER, and SNP&amp;GO identified several potentially deleterious variants, with rs201763454 (L156F) notably predicted to impair protein function. Conservation analysis with ConSurf revealed that key residues such as H126Y and A223S are highly conserved, indicating their functional importance. Homology-based structural modeling via Phyre2 indicated SNP-induced alterations in secondary structure, while stability and flexibility assessments suggested destabilizing effects for multiple variants. Structural mapping confirmed that high-risk SNPs are localized within critical functional domains of <em>SOCS3</em>. CScape cancer susceptibility prediction revealed that E98V and A223S as oncogenic SNPs. Further analysis using cBioPortal and CanSAR Black confirmed the involvement of E98V and other variants (S26N, F136L, A223S) in various cancers, highlighting their potential clinical significance. Protein-protein interaction analyses (STRING, GeneMANIA) further highlighted the biological relevance. Collectively, this study identifies critical <em>SOCS3</em> SNPs that may modulate protein function and contribute to MFD pathogenesis. These findings suggest that <em>SOCS3</em> missense SNPs, particularly E98V, H126Y, and A223S, may serve as candidate biomarkers for cancer susceptibility and warrant further experimental validation</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"832 ","pages":"Article 111925"},"PeriodicalIF":1.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145770351","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}