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

{"title":"miR-145-5p induces ferroptosis by targeting Notch2 to suppress melanoma progression","authors":"Xinghui Li,&nbsp;Yannan Jiang,&nbsp;Yanxia Ding,&nbsp;Pingping Qin","doi":"10.1016/j.mrfmmm.2026.111942","DOIUrl":"10.1016/j.mrfmmm.2026.111942","url":null,"abstract":"<div><h3>Background</h3><div>Melanoma exhibits high malignancy with limited treatment options, while the newly defined type of programmed cell death, ferroptosis, presents a promising therapeutic avenue for melanoma. Notch2 has been implicated as a pivotal regulator of ferroptosis, yet its impact on melanoma and the upstream regulation remain elusive.</div></div><div><h3>Methods</h3><div>The TCGA data were used to correlate Notch2 expression with patient prognosis. Potential binding sites of miR-145–5p and Notch2 were predicted with starbase database. The levels of Notch2 and miR-145–5p in human melanoma tissues and cell lines were quantified via RT-qPCR, and their expression correlation was calculated. A875 cells were treated with si-Notch2 or ferrostatin-1. GSH content, GPX4 activity, ferrous ion level, cell viability, mortality and apoptosis were measured to evaluate the influence of Notch2 expression on ferroptosis and cell viability. Dual-luciferase reporter assays were involved to verify direct binding of miR-145–5p and Notch2 3’UTR. The miR-145–5p mimic or oe-Notch2 was transfected into A875 cells to validate the mechanism of miR-145–5p promoting ferroptosis in melanoma via Notch2.</div></div><div><h3>Results</h3><div>Notch2 was markedly upregulated in melanoma and associated with poor survival. Knockdown of Notch2 activated ferroptosis and attenuated cell viability. miR-145–5p bound the Notch2 3’UTR and repressed its expression. Overexpression of miR-145–5p reversed Notch2-mediated ferroptosis resistance, elevated cell death, and augmented apoptosis.</div></div><div><h3>Conclusion</h3><div>miR-145–5p targets Notch2 to activate ferroptosis and curb melanoma progression. The study offers a novel therapeutic rationale for ferroptosis-based melanoma treatment.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"833 ","pages":"Article 111942"},"PeriodicalIF":2.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148414452","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 role of KIT mutations in oral melanoma and disease progression: A literature review on early detection and targeted therapy","authors":"Sai Priyankha,&nbsp;Dhanraj Ganapathy,&nbsp;Smitha Nair,&nbsp;Pitchiah Sivaperumal","doi":"10.1016/j.mrfmmm.2026.111946","DOIUrl":"10.1016/j.mrfmmm.2026.111946","url":null,"abstract":"<div><div>Oral melanoma is a rare and aggressive subtype of melanoma that presents significant challenges in terms of delayed diagnosis and treatment. One promising clinical outcome is the detection of <em>KIT</em> gene mutations, which play a key role in tumor proliferation and resistance to therapy. The <em>KIT</em> gene encodes a receptor tyrosine kinase critical for cell survival and proliferation, and its mutations are associated with more aggressive tumor behavior. Detection of <em>KIT</em> mutations can be achieved through techniques such as tissue biopsy, next-generation sequencing (NGS), RT-PCR, and immunohistochemistry, providing comprehensive genomic profiling and insights into potential therapeutic targets. Precision therapies, including small-molecule inhibitors like imatinib and sunitinib, as well as combination therapies involving immune checkpoint inhibitors, offer personalized treatment strategies. Despite the potential, the rarity of oral melanoma limits clinical trials, and understanding resistance mechanisms remains a significant challenge for effective treatments for oral melanoma patients. This article highlights the critical role of <em>KIT</em> mutations in oral melanoma, offering insights into how molecular diagnostics can pave the way for personalized treatment approaches by focusing on advanced detection techniques and targeted therapies.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"833 ","pages":"Article 111946"},"PeriodicalIF":2.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148703171","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":"Potential targets and molecular mechanisms of curcumin in treating Laryngeal and Pharyngeal Carcinoma throat cancer based on network pharmacology and bioinformatics analysis","authors":"Jixiang Lei,&nbsp;Xianyun Tang,&nbsp;Yuanchao Lin,&nbsp;Rui Yang,&nbsp;Zhiyue Ma","doi":"10.1016/j.mrfmmm.2026.111943","DOIUrl":"10.1016/j.mrfmmm.2026.111943","url":null,"abstract":"<div><h3>Background</h3><div>Curcumin exhibits significant antitumor activity, inhibiting proliferation, angiogenesis, invasion, and metastasis, highlighting its potential for cancer treatment. However, its mechanisms in Laryngeal and Pharyngeal Carcinoma remain unclear. Therefore, this study aims to elucidate these mechanisms through <em>in vitro</em> and <em>in vivo</em> experiments.</div></div><div><h3>Methods</h3><div>Cell functions were examined using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), 5-Ethynyl-2’-deoxyuridine (EdU) staining, tube formation assay, flow cytometry, and Transwell assays. Laryngeal and Pharyngeal Carcinoma-related genes were screened using GeneCards database, while curcumin-related genes were predicted using TCMSP and Swiss Target Prediction databases. Enrichment analysis of overlapping genes was performed using KEGG and GO analysis. Additionally, the core genes from common target genes were analyzed using Cytoscape and its plugins Cytohubba and MCODE. Gene expression was detected using reverse transcription-quantitative polymerase chain reaction (qRT-PCR) and western blot. Molecular docking was used to computationally predict the binding affinity between curcumin and EP300, followed by normal mode analysis (NMA)-based simulation to hypothetically explore complex stability under equilibrium conditions as a static approximation. Xenograft tumor models were constructed to investigate the role of curcumin and EP300.</div></div><div><h3>Results</h3><div>Curcumin suppressed Laryngeal and Pharyngeal Carcinoma cell proliferation, migration, and invasion, and HUVEC tube formation, and promoted cancer cell apoptosis. Six of the eight curcumin-targeted genes were overexpressed in Laryngeal cancer (in both datasets), with NFE2L2 non-significantly upregulated and BCL2 showing heterogeneous expression. EP300 expression was increased in Laryngeal and Pharyngeal Carcinoma tissues and cells, and curcumin inhibited EP300 expression. Molecular docking, coupled with NMA, predicted favorable binding affinity and suggested that the curcumin and EP300 histone acetyltransferase (HAT) domain complex forms a stable binding mode. Notably, curcumin suppressed Laryngeal and Pharyngeal Carcinoma cell proliferation, migration, invasion, and HUVEC tube formation, and promoted cancer cell apoptosis in a process involving EP300, as demonstrated by rescue experiments with EP300 overexpression. In addition, EP300 overexpression reversed the inhibitory effect of curcumin on tumor growth.</div></div><div><h3>Conclusion</h3><div>Curcumin inhibits FaDu and AMC-HN-8 cell proliferation, HUVEC tube formation, cancer cell migration, and invasion and promotes cell apoptosis in a process involving EP300, as demonstrated by EP300 overexpression rescue experiments.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"833 ","pages":"Article 111943"},"PeriodicalIF":2.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148474993","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":"Molecular characterisation and mutational analysis of antimicrobial resistance genes in Helicobacter pylori isolates in Erbil, Iraq","authors":"Karwan I. Othman,&nbsp;Ahang H. Mawlood,&nbsp;Salah Tofik Jalal Balaky,&nbsp;Mostafa Rahnama,&nbsp;Mukhtar H. Ahmed,&nbsp;Nazar P. Shabila","doi":"10.1016/j.mrfmmm.2026.111948","DOIUrl":"10.1016/j.mrfmmm.2026.111948","url":null,"abstract":"<div><h3>Background</h3><div>Antibiotic resistance in <em>Helicobacter pylori</em> poses a significant challenge to the effective eradication of infection worldwide. Understanding molecular mechanisms of resistance is essential for guiding treatment strategies. This study aimed to investigate the molecular basis of antimicrobial resistance in <em>Helicobacter pylori</em> isolates and their associated mutation frequencies.</div></div><div><h3>Methods</h3><div>In this cross-sectional study, gastric biopsy specimens were collected from 203 patients at Rizgary Hospital in Erbil, Kurdistan Region, Iraq, who underwent endoscopy for dyspepsia-related symptoms. Of the 137 positive patients, 91 <em>Helicobacter pylori</em> isolates were confirmed by colony morphology, Gram staining, and biochemical tests; 63 were successfully subcultured for antimicrobial susceptibility testing (culture success rate: 69.2%). Antimicrobial susceptibility testing was performed by the agar dilution method to determine the minimum inhibitory concentrations. The sequences of specific genes were examined and analysed by next-generation sequencing. Multiple sequence comparisons were performed to identify resistance-related genes and mutations, using 26695 (NC_000915.1) as the reference genome.</div></div><div><h3>Results</h3><div>Only two isolates (3.17%) were susceptible to all antibiotics examined. The frequency of metronidazole resistance was highest (85.71%), followed by levofloxacin (55.55%), clarithromycin (52.38%), amoxicillin (26.98%), tetracycline (6.35%), and rifabutin (4.76%). Mutations in the <em>rdxA</em> and <em>frxA</em> genes correlated with metronidazole resistance, while GyrA protein mutations at positions 87 and 91 were linked to levofloxacin resistance. Clarithromycin resistance was mainly associated with A2142G and A2143G mutations in 23S rRNA. Amoxicillin resistance (26.98%) was associated with mutations in the <em>pbp1A</em> gene, whereas resistance to tetracycline and rifabutin was infrequent. Conclusions: This study provides the first molecular surveillance data on <em>antimicrobial resistance in Helicobacter pylori</em> in northern Iraq, offering valuable regional evidence to guide local eradication strategies. The relatively high amoxicillin resistance, together with the elevated resistance to metronidazole, levofloxacin, and clarithromycin, underscores the need for susceptibility-guided therapy and continuous local antimicrobial resistance surveillance.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"833 ","pages":"Article 111948"},"PeriodicalIF":2.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148898753","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":"A crosslinking positive control for any in vivo comet assay tissue","authors":"Marie Z. Vasquez,&nbsp;Nicole E. Dewhurst,&nbsp;Kaylee O’Hora,&nbsp;Kathryn Heatherly","doi":"10.1016/j.mrfmmm.2026.111949","DOIUrl":"10.1016/j.mrfmmm.2026.111949","url":null,"abstract":"<div><div>OECD TG 489 recognizes that some modifications of the <em>in vivo</em> comet assay (e.g., longer electrophoresis times) can detect DNA crosslink inductions expressed as DNA migration decreases. But the application of these methods in regulated safety testing has been limited because identifying an <em>in vivo</em> crosslinking positive control for every tissue that can be evaluated with the comet assay can be very challenging. Most crosslinking agents induce crosslinks in just one tissue (e.g., site of contact) with the agent’s toxicity limiting exposure and effects induced in other tissues. This complication can require different positive control compounds with additional animals for each compound to adequately evaluate crosslinks in the multiple tissues typically evaluated with the comet assay. Our objective was to develop a method for generating concurrent <em>in vivo</em> crosslinking positive control comet data for any tissue without using additional animals. We accomplished this by preparing for each tissue evaluated extra comet slides from the conventional positive control (EMS) dosed animals and <em>ex</em> vivo crosslinking the heavily damaged cells on these slides with 10% neutral buffered formalin (NBF) immediately before lysis. These <em>ex vivo</em> crosslinked slides were then electrophoresed with the rest of the study slides with the same standard conditions and electrophoresis time. The conventional comet study slides prepared from the liver, duodenum, glandular stomach, and lung tissues collected from the EMS dosed animals and lysed without <em>ex vivo</em> crosslinking expressed a statistically significant DNA migration increase when compared to the concurrent vehicle control dose group. The <em>ex vivo</em> crosslinked slides from the EMS dose group tissue samples expressed a statistically significant decrease in DNA migration when compared to the concurrent vehicle control group. Although no statistical analysis was conducted, it is clear by the data that the <em>ex vivo</em> crosslinked slides from the EMS dose group tissue samples also expressed a significant decrease compared to the same samples from the EMS dose group without the <em>ex vivo</em> NBF treatment. This data demonstrate that the method can be easily incorporated into any existing comet study design to evaluate crosslink induction in any comet assay tissue with minimal effort or cost and without the use of any additional animals.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"833 ","pages":"Article 111949"},"PeriodicalIF":2.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148946474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mothers against decapentaplegic homolog 3-activated FAT atypical cadherin 2 regulates programmed death ligand-1 to mediate immune evasion in lung squamous cell carcinoma","authors":"Yuanqiang Zhang,&nbsp;Chunping Yang,&nbsp;Haowen Deng,&nbsp;Xiaokang Chen,&nbsp;Huajie Tong","doi":"10.1016/j.mrfmmm.2026.111945","DOIUrl":"10.1016/j.mrfmmm.2026.111945","url":null,"abstract":"<div><h3>Background</h3><div>Lung squamous cell carcinoma (LUSC) represents a distinct subtype of lung cancer, diverging significantly from lung adenocarcinoma. It demonstrates the ability to evade the immune system before the tumor has even begun to infiltrate. However, our understanding of these immune evasion mechanisms in LUSC is still in its infancy, calling for more intensive research.</div></div><div><h3>Methods</h3><div>The expression levels of FAT atypical cadherin 2 (FAT2) and mothers against decapentaplegic homolog 3 (SMAD3) in LUSC were assessed by bioinformatics analysis, with the correlation between FAT2 and CD8⁺ T cell infiltration examined. The FAT2 expression and immune cell infiltration in clinical samples were analyzed via immunohistochemistry. FAT2, SMAD3, and programmed death ligand-1 (PD-L1) expressions were determined using quantitative reverse transcriptase polymerase chain reaction. The interplay between FAT2 and SMAD3 was elucidated through chromatin immunoprecipitation and dual-luciferase reporter gene assays. The mechanism by which FAT2 activates the Wnt/β-catenin pathway to induce PD-L1 expression was further validated by TOPFlash/FOPFlash dual-luciferase reporter assays and chromatin immunoprecipitation followed by quantitative PCR. After culturing tumor cells alongside CD8⁺ T cells, the effect of SMAD3-activated FAT2 on PD-L1-mediated immune escape was tested through Cell Counting Kit-8 and lactate dehydrogenase detection and evaluated by enzyme-linked immunosorbent assay. The rescue experiments were designed by introducing Wnt pathway inhibitors to determine whether FAT2 affected PD-L1 expression through the Wnt pathway. Based on a mouse transplant tumor model, we verified the effect of knockdown of FAT2 and combination therapy with anti-PD-L1 on tumor growth.</div></div><div><h3>Results</h3><div>An upregulation of FAT2 in LUSC was observed, which showed a negative correlation with CD8⁺ T cell infiltration. High FAT2 expression was linked to increased PD-L1 levels, which suppressed the anti-tumor immune function of CD8⁺ T cells. SMAD3 was found to bind to the FAT2 promoter, stimulating its transcription. Rescue experiments illustrated that FAT2 overexpression could neutralize the positive impact of SMAD3 knockdown on the immune response of CD8⁺ T cells. In further research, FAT2 was found to mainly promote PD-L1 expression by activating the Wnt pathway. In addition, animal experiments demonstrated that the combination therapy of knocking down FAT2 and anti-PD-L1 significantly repressed LUSC growth.</div></div><div><h3>Conclusion</h3><div>In summary, this study elucidated the important role of SMAD3 activation of FAT2 expression in LUSC immune escape and proposed a combined immune strategy targeting the FAT2/PD-L1 axis. The study can provide a new direction for the clinical intervention of LUSC.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"833 ","pages":"Article 111945"},"PeriodicalIF":2.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148631958","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":"Biochemical analysis of APOBEC3A-induced mutational signatures and clustered mutagenesis","authors":"Tomohiko Sugiyama,&nbsp;Helena Littler,&nbsp;Eden Kenner,&nbsp;Elaina Grube,&nbsp;Chukwunweike Odiaka,&nbsp;Mya Crestwell,&nbsp;Sasmitha Baskaran","doi":"10.1016/j.mrfmmm.2026.111950","DOIUrl":"10.1016/j.mrfmmm.2026.111950","url":null,"abstract":"<div><div>APOBEC3A is a single-stranded DNA cytidine deaminase that is involved in mutagenic processes in various cancers. Ample evidence indicates that APOBEC3A causes two major mutational signatures (SBS2 and SBS13) in cancer cells and cellular model systems, but the detailed molecular mechanisms that generate these two signatures from a single deaminase remain unclear. APOBEC3A-induced mutations are preferentially observed at DNA hairpin structures and are often observed as clusters in cancer genomes, but the molecular mechanisms behind the clustered mutations are unclear. Here, we developed a cell-free system to analyze the mutations on APOBEC3A-treated DNA and successfully reproduced SBS2 and a portion of SBS13 by using specific combinations of DNA polymerases. While SBS2 can be produced by a replicative DNA polymerase, SBS13 requires the activities of uracil DNA glycosylase, Rev1, and Pol ζ. We also found that the DNA hairpin structures have positive and negative influences on deaminase activity depending on the position of cytosine residues within the loop. In our system, APOBEC3A-induced mutagenesis showed positive cooperativity by which one mutation stimulated a second mutation at up to 50-nt distance. This cooperative effect promoted clustered mutagenesis <em>in vitro</em>, but little continuity of mutations was observed among the multi-mutation products. These observations support an aggregation-mediated mechanism of clustered mutagenesis.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"833 ","pages":"Article 111950"},"PeriodicalIF":2.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149121373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deuterium enhances mutation fixation in Escherichia coli through a transition-biased mechanism","authors":"Katsuya Satoh,&nbsp;Yoshihiro Hase,&nbsp;Naoya Shikazono","doi":"10.1016/j.mrfmmm.2026.111951","DOIUrl":"10.1016/j.mrfmmm.2026.111951","url":null,"abstract":"<div><div>Deuterium (D) alters biochemical reaction kinetics through the hydrogen/deuterium kinetic isotope effect (KIE), but its role in spontaneous mutagenesis remains controversial. Here, we investigated the effects of deuterium on mutagenesis in <em>Escherichia coli</em> strains AB1157 and BMH71–18 under either deuterium-labeled medium (<span>D</span>-broth) or unlabeled medium (H-broth) conditions. The growth rates of both strains in <span>D</span>-broth were reduced by 2.77- and 3.90-fold, respectively, compared with those in H-broth. Stationary-phase viability was not significantly affected in either strain, indicating that deuterium inhibits growth kinetically rather than through cytotoxicity. Spontaneous mutation frequency was evaluated using rifampicin resistance (Rifᴿ). A significant 5.57-fold increase in Rif^R mutant frequency was observed in BMH71–18 under deuterated conditions, whereas no significant increase was detected in AB1157. Whole-genome sequencing was therefore focused on BMH71–18, the strain showing the clearest mutational response to deuteration. Whole-genome sequencing of randomly selected colonies revealed a 5.35-fold increase in mutation events under deuterated conditions. Single-base substitutions predominated in both conditions, with transition mutations accounting for more than 90% of all substitutions. In contrast, no significant differences were detected in transversions, small insertions, deletions, or structural variants. These findings are consistent with the possibility that deuterium promotes mutation fixation by prolonging the persistence of rare tautomeric states during DNA replication. Collectively, our results suggest that deuterium enhances mutation fixation in <em>E. coli</em> rather than acting as a primary mutagen and is associated with a strongly transition-biased mutation spectrum.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"833 ","pages":"Article 111951"},"PeriodicalIF":2.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149139943","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 silico analysis of missense variants in functional domains of PWWP2A and PWWP2B proteins","authors":"Murugesan Selvamani,&nbsp;Bazeer Asbar Banu,&nbsp;Mahesh Samantaray,&nbsp;M.N. Meenu,&nbsp;Jawahar Ramasamy,&nbsp;Subramanian Vasudevan Srinivasan,&nbsp;Sambandam Ravikumar,&nbsp;Irisappan Ganesh","doi":"10.1016/j.mrfmmm.2026.111947","DOIUrl":"10.1016/j.mrfmmm.2026.111947","url":null,"abstract":"<div><div>Epigenetic regulatory activity through chromatin remodelling is essential for maintaining gene expression integrity, and alterations in chromatin-associated proteins can cause pathological consequences. The conserved PWWP domain in PWWP2A and PWWP2B, which are Royal family of chromatin readers, can recognize methylated histones and regulate transcriptional mechanisms. Beyond their biological significance, the structural effects of missense mutations in the PWWP2A and PWWP2B domains remain unknown. No previous study has been done on the effect of missense mutations in PWWP2A and PWWP2B that affect their stability, folding, chromatin-interacting functions. To predict pathogenicity and structural disruption, in silico characterization of missense mutations was conducted in both genes using SIFT, PolyPhen-2, GERP, Mutation Assessor, MutPred, I-Mutant 2.0, Project HOPE. As a result, 354 and 352 missense variants were obtained from 1712 and 1301 SNPs in PWWP2A and PWWP2B, respectively. Of which, fifteen missense variants were recognized as highly pathogenic: 11 in PWWP2A (R195W, G650D, V655A, D657H/G, A661D, L674V, R680W, W695R, F716V, Y728C) and 4 in PWWP2B (P505L, A506V, Y563C, R564W). These mutations changed the protein's hydrophobic and electrostatic properties and reduced stability. They occur on conserved residues of the PWWP domain, indicating possible link to disease mechanisms. Furthermore, AlphaFold2-based 3D modelling and Ramachandran plot analysis indicated potential misfolding and domain perturbations. To conclude, this study proposes a predictive structural framework to understand the impact of missense mutations in the PWWP2A and PWWP2B domains on transcriptional regulation and chromatin binding; further experimental validation will be required to confirm the effects predicted in this study. The integrative computational approach of this study provides a foundation for experimental validation and therapeutic investigation of PWWP2-associated disorders.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"833 ","pages":"Article 111947"},"PeriodicalIF":2.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148803932","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":"Non-clonal interphase markers of chromosomal instability in malignancy acquisition and cancer progression","authors":"Vinícius Bernardo de Oliveira,&nbsp;João Marcos Oliveira-Silva,&nbsp;Giovanna De Souza Maciel,&nbsp;Marcos Samuel Souza Paulino,&nbsp;Laís Bernardo Lopes,&nbsp;Larissa Pereira Damasceno,&nbsp;Maria Eduarda do Vale Uliniki Teixeira,&nbsp;Angel Mauricio Castro-Gamero","doi":"10.1016/j.mrfmmm.2026.111944","DOIUrl":"10.1016/j.mrfmmm.2026.111944","url":null,"abstract":"<div><div>Chromosomal instability (CIN) is a pervasive feature of cancer and a major driver of tumor heterogeneity, evolution, and therapeutic resistance. Arising predominantly from defects in chromosome segregation, DNA repair, and mitotic fidelity, CIN promotes continuous genomic diversification within tumor cell populations, enabling adaptive responses to intrinsic and extrinsic selective pressures. While clonal chromosomal alterations reflect stabilized genomic configurations selected during tumor evolution, non-clonal interphase markers of chromosomal instability represent transient, low-frequency events that capture ongoing microevolutionary dynamics and genomic plasticity. This review provides a comprehensive synthesis of current knowledge regarding both classical and non-classical markers of CIN evaluated during interphase, including micronuclei, nucleoplasmic bridges, nuclear buds, cytoplasmic chromatin, massive chromosomal segregation errors, chromosomal fragmentation, and genomic chaos-related phenomena. We discuss the cellular mechanisms underlying their formation, their contribution to structural and numerical chromosomal alterations, and their role in shaping intratumoral heterogeneity, adaptive potential, malignancy acquisition, and cancer progression. Particular emphasis is placed on the \"just-right\" dual nature of CIN, which can either drive tumor aggressiveness or precipitate mitotic catastrophe and cell death, depending on its magnitude and cellular context. By integrating cytogenetic, molecular, and evolutionary perspectives, this review highlights the relevance of these non-clonal interphase cytogenetic markers as sensitive indicators of genome instability and tumor dynamics. Understanding the interplay between clonal and non-clonal chromosomal alterations may provide valuable insights for the development of prognostic tools and therapeutic strategies aimed at exploiting the vulnerabilities of genomically unstable cancers.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"833 ","pages":"Article 111944"},"PeriodicalIF":2.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148458280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}