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

{"title":"Deciphering the molecular mechanism of YY1/HIF1A modulating ovarian cancer angiogenesis based on single-cell transcriptomics technology","authors":"Xiyun Quan ,&nbsp;Huimei Yi ,&nbsp;Meiyuan Huang,&nbsp;Dongliang Chen","doi":"10.1016/j.mrfmmm.2025.111916","DOIUrl":"10.1016/j.mrfmmm.2025.111916","url":null,"abstract":"<div><h3>Background</h3><div>Angiogenesis assumes an essential role in tumor development and is a fundamental condition for tumor growth. Yin Yang 1 (YY1) is highly expressed in various types of cancers and is a key player in tumor angiogenesis, but its role in ovarian cancer (OC) has not been fully elucidated. Therefore, this study will delve into the mechanism of YY1 in OC angiogenesis.</div></div><div><h3>Methods</h3><div>Based on single-cell transcriptomics data of OC tumor samples and adjacent samples downloaded from the GEO database, differentially expressed genes (DEGs) and related signaling pathways were screened and validated in OC cells. Furthermore, co-culture technology was applied to assess the impact of YY1 expression in OC cells on angiogenesis ability. The molecular mechanism of YY1 regulation of OC angiogenesis was explored through bioinformatics analysis combined with co-immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter gene assays. Rescue experiments were designed, with results validated in qRT-PCR, angiogenesis assays, and Western blotting.</div></div><div><h3>Results</h3><div>Based on re-analysis of single-cell transcriptomics data from OC tumor samples and adjacent samples, we found that YY1 expression was significantly upregulated in OC cells, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis results showed that DEGs in YY1-positive tumor cells were significantly enriched in the HIF-1 signaling pathway. Moreover, <em>in vitro</em> experiments demonstrated that YY1 was highly expressed in OC to boost OC angiogenesis. Specifically, YY1 can stabilize hypoxia-inducible factor 1α (HIF1A) expression by competitively binding to WD repeat domain-containing 7 (FBXW7), thereby facilitating the transcriptional activation of angiogenesis genes. Finally, we demonstrated through rescue experiments that targeting the YY1/HIF1A axis can repress OC angiogenesis.</div></div><div><h3>Conclusion</h3><div>Through single-cell transcriptomics analysis combined with cell experiments, we proved the specific mechanism by which YY1 affects the angiogenesis ability of OC. YY1 affects the expression of angiogenesis genes by modulating the FBXW7/HIF1A axis.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111916"},"PeriodicalIF":1.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145265771","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":"WTAP-mediated m6A modification of ARG2 mRNA Inhibits Its expression and drives prostate cancer malignant progression","authors":"Jianxin Li ,&nbsp;Yu Zheng ,&nbsp;Chaojiang Chen ,&nbsp;Zhuoyuan Lin ,&nbsp;Jiangang Pan ,&nbsp;Funeng Jiang ,&nbsp;Weide Zhong","doi":"10.1016/j.mrfmmm.2025.111912","DOIUrl":"10.1016/j.mrfmmm.2025.111912","url":null,"abstract":"<div><h3>Background</h3><div>Prostate cancer (PCa) incidence increases as age advances and seriously endangers men’s health worldwide. Arginase 2 (ARG2) has been identified as a potential diagnostic and prognostic marker for PCa. However, the molecular mechanisms underlying its function in PCa remain undefined.</div></div><div><h3>Methods</h3><div>ARG2 mRNA and protein expression were quantified in PCa tissues and cells using qRT-PCR and Western blot. Cellular proliferation, glucose consumption, lactate production, apoptosis, and ferroptosis were evaluated via EdU incorporation, colony formation assays, commercial kits, and flow cytometry. Subsequently, the xenograft model was established to assess ARG2’s role in tumor growth <em>in vivo</em>. Bioinformatics analysis and RNA immunoprecipitation (RIP) were employed to investigate the interaction between Wilms’ tumor 1-associating protein (WTAP), a key component of the N6-methyladenosine (m6A) methyltransferase complex, and ARG2 mRNA. Besides, mRNA stability was determined using actinomycin D chase assays.</div></div><div><h3>Results</h3><div>ARG2 exhibited low expression in PCa tissues and cells. Upregulation of ARG2 inhibited proliferation and glycolysis, and promoted apoptosis, oxidative stress and ferroptosis of PCa cells. However, silencing ARG2 had the opposite effects. I<em>n vivo</em>, ARG2 overexpression suppressed tumor growth. Mechanistically, WTAP bound directly to ARG2 mRNA, and their expression levels were inversely correlated. WTAP knockdown phenocopied ARG2 overexpression by repressing proliferation and glycolysis and enhancing apoptosis/ferroptosis, effects reversed by ARG2 silencing. ARG2 overexpression counteracted the oncogenic effects of WTAP overexpression.</div></div><div><h3>Conclusion</h3><div>WTAP bound to ARG2 and suppressed its expression, thereby promoting the malignant progression of PCa.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111912"},"PeriodicalIF":1.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144750383","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":"DGKβ accelerates the progression of cervical cancer through ANGPT4-mediated tumor angiogenesis","authors":"Qing Li,&nbsp;Zhenyu Zhou,&nbsp;Xiaoying Li,&nbsp;Qiongyu Lan","doi":"10.1016/j.mrfmmm.2025.111913","DOIUrl":"10.1016/j.mrfmmm.2025.111913","url":null,"abstract":"<div><h3>Background</h3><div>Cervical cancer (CC) is a major cause of morbidity and mortality in women, with complex etiology and progression. Diacylglycerol kinases (DGKs) are pivotal in lipid metabolism. Although diacylglycerol kinase beta (DGKβ) is well-studied in neurology, its role in cancer, especially CC, remains underexplored. This study aimed to explore DGKβ's role and mechanism in CC.</div></div><div><h3>Methods</h3><div>Bioinformatics analysis was employed to identify genes differentially expressed in CC, with western blot confirming DGKβ expression in CC cells. The role of DGKβ was examined through small interfering RNA-mediated gene silencing, proliferation tests, migration and invasion assays, and angiogenesis studies. In-depth bioinformatics explored DGKβ-regulated downstream targets and pathways. Pathological assessment elucidated the impact of DGKβ and angiopoietin 4 (ANGPT4) on CC samples.</div></div><div><h3>Results</h3><div>Our data identified DGKβ as a promising candidate gene in the context of CC. This conclusion stemmed from the notable observation that DGKβ exhibited a heightened expression in CC cell lines. Notably, the silencing of DGKβ resulted in the suppression of CC cell proliferation, invasion, migration, as well as the epithelial-mesenchymal transition processes. Additional bioinformatics analysis delving into DGKβ-associated genes revealed ANGPT4 as a downstream target gene of DGKβ, which is capable of modulating angiogenesis and possesses multiple cellular functions related to cell survival, proliferation, and migration. Most significantly, our findings also demonstrated that both DGKβ and ANGPT4 were overexpressed in clinical specimens of CC.</div></div><div><h3>Conclusion</h3><div>This study uncovered an oncogenic role for DGKβ in CC and identified a potential regulatory link between DGKβ and ANGPT4 in tumor angiogenesis. These findings provided promising directions for developing new diagnostic and therapeutic approaches for CC.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111913"},"PeriodicalIF":1.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144827773","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":"Hypoxia-induced HIF-1α enhanced the tumorigenesis in non-small cell lung cancer by targeting GAB2","authors":"Xunxia Zhu ,&nbsp;Xiaoyong Shen ,&nbsp;Xiaoyu Chen,&nbsp;Xuelin Zhang,&nbsp;Wen Gao","doi":"10.1016/j.mrfmmm.2025.111917","DOIUrl":"10.1016/j.mrfmmm.2025.111917","url":null,"abstract":"<div><div>Non-small cell lung cancer (NSCLC) is a lethal disease with high morbidity and mortality rates. HIF-1α is confirmed to be involved in NSCLC. However, the detailed mechanism of its role remains unclear. NCI-H226 and SK-MES-1 cell lines were used to explore the mechanisms by which hypoxia affects the progression of NSCLC <em>in vitro</em>. The cellular functions were detected by transwell. The expressions of key biomarkers were examined by Real-time quantitative reverse transcription PCR (qRT-PCR) and Western Blot assays. The RNA sequencing analysis was used to explore the downstream targets of HIF-1α. Luciferase and Chromatin immunoprecipitation (ChIP) assays confirmed the interaction between HIF-1α and GAB2. What’s more, the xenograft model was used to investigate the effect of GAB2 <em>in vivo</em>. Hypoxia promoted the migration and invasion capabilities of NCI-H226 and SK-MES-1 cells. RNA sequencing analysis revealed that the expression of GAB2 is dramatically altered under a hypoxic environment. The bioinformatics analysis implied that the differentially expressed genes (DEGs) were enriched in the MEK/ERK signaling pathway and the significantly expressed GAB2 was associated with HIF-1α. Functionally, GAB2 regulated migration and invasion capabilities in vitro and facilitated tumor growth and lung metastasis of NSCLC <em>in vivo</em>. What’s more, luciferase and ChIP assays further demonstrated that HIF-1α could bind to GAB2<strong>.</strong> Hypoxia-induced HIF-1α enhanced tumor growth and lung metastasis in NSCLC by targeting GAB2, which might provide novel insights into GAB2 as a potential therapeutic target for NSCLC.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111917"},"PeriodicalIF":1.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145265770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of TERT promoter hotspot mutations using droplet digital PCR in hepatoblastoma and hepatocellular carcinoma","authors":"Yoko Hiyama ,&nbsp;Masato Kojima ,&nbsp;Sho Kurihara ,&nbsp;Isamu Saeki ,&nbsp;Ryo Touge ,&nbsp;Takahiro Fukazawa ,&nbsp;Takanori Harada ,&nbsp;Eiso Hiyama","doi":"10.1016/j.mrfmmm.2025.111915","DOIUrl":"10.1016/j.mrfmmm.2025.111915","url":null,"abstract":"<div><div>Somatic mutations in the telomerase reverse transcriptase promoter (<em>TERT</em>p) region are common in many cancers, including in liver cancers. Detection of <em>TERT</em>p mutations in tumor tissue DNAs and cell-free tumor DNAs is useful for diagnosing and monitoring cancers. Since the most common <em>TERT</em>p hotspot mutations, C228T and C250T, are difficult to identify using Sanger sequencing, we tested an easy and highly sensitive alternative method that targets these two sites using droplet digital PCR. Using this method, both the sensitivity and specificity for detecting these two mutations were 100 % in DNA samples derived from cell lines and liver cancer tissues, including hepatocellular carcinoma (HCC) and hepatoblastoma (HB). The detection limit for the allele frequencies of these mutations was approximately 0.1 %. This method is also widely applicable; for instance, it can be applied to DNA derived from FFPE (formalin-fixed paraffin embedded) samples. In addition, we applied this method to detecting <em>TERT</em>p mutations in cell-free DNA samples of patients with <em>TERT</em>p-mutated tumors. Finally, we found that outcomes for HB patients with <em>TERT</em>p mutations were significantly worse than in those without mutations, indicating the importance of this method for improving patient outcomes. In light of this, we discuss the advantages of this method for clinical implementation in the detection and monitoring of cancers.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111915"},"PeriodicalIF":1.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145108771","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 novel mechanism in driving non-small cell lung cancer progression: The METTL3/FOXA1/PTK2 cascade","authors":"Xuelin Zhang ,&nbsp;Yizhao Chen ,&nbsp;Lingjie Wang ,&nbsp;Qingyue Lin ,&nbsp;Tingjian Li ,&nbsp;Chunya He","doi":"10.1016/j.mrfmmm.2025.111911","DOIUrl":"10.1016/j.mrfmmm.2025.111911","url":null,"abstract":"<div><h3>Background</h3><div>Dysregulation of m6A modification has significant implications in human carcinogenesis. METTL3, a crucial m6A writer, acts as an oncogenic driver in non-small cell lung cancer (NSCLC). Here, we explored its mechanisms in driving NSCLC development.</div></div><div><h3>Methods</h3><div>Cell sphere formation, invasion, apoptosis, and proliferation were detected by sphere formation, transwell, flow cytometry, and MTT assays, respectively. Cell glycolysis was evaluated by measuring glucose consumption, lactate production, and ATP/ADP ratio. RIP, methylated RIP (MeRIP), and mRNA stability assays were used to analyze the METTL3/FOXA1 relationship. Luciferase assay and ChIP experiment were used for the evaluation of the FOXA1/PTK2 relationship. Xenograft studies were used to test the role <em>in vivo</em>.</div></div><div><h3>Results</h3><div>METTL3 was upregulated in NSCLC, and its inhibition diminished the growth, invasiveness, sphere formation ability, and glycolysis of H1299 and A549 cells. Mechanistically, METTL3 depletion caused a reduction in FOXA1 expression through the m6A modification mechanism. FOXA1 transcriptionally controlled PTK2 expression. FOXA1 upregulation reversed the effects of METTL3 inhibition on the growth, invasiveness, sphere formation ability, and glycolysis of H1299 and A549 cells. Moreover, FOXA1 increase attenuated the impact of METTL3 inhibition on the <em>in vivo</em> growth of A549 subcutaneous xenografts. Additionally, increased PTK2 expression counteracted the effects of FOXA1 reduction on the malignant phenotypes of H1299 and A549 cells.</div></div><div><h3>Conclusion</h3><div>Our finding elucidates a novel mechanism for METTL3’s oncogenic activity in NSCLC, where METTL3 upregulates FOXA1 and thus activates PTK2 transcription. Blocking this cascade may be effective for combating NSCLC.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111911"},"PeriodicalIF":1.5,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144312897","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":"METTL14-mediated m6A modification of ETV4 inhibits tumor development in colorectal cancer","authors":"Xiaofeng Liao,&nbsp;Tao Hu","doi":"10.1016/j.mrfmmm.2025.111910","DOIUrl":"10.1016/j.mrfmmm.2025.111910","url":null,"abstract":"<div><h3>Background</h3><div>Many m6A methyltransferases have been identified to regulate colorectal cancer (CRC) progression. METTL14 has been confirmed to play a negative role in CRC process, but the molecular mechanism of METTL14 in regulating CRC progression needs to be further elucidated.</div></div><div><h3>Methods</h3><div>The levels of METTL14, YTHDF2 and ETS translocation variant 4 (ETV4) were examined by qRT-PCR and western blot. Cell proliferation and apoptosis were determined by colony formation assay and flow cytometry. Cell glycolysis was assessed by detecting corresponding indicators. Cell ferroptosis was evaluated via measuring SOD, MDA, GSH, ROS and Fe^2 + levels. The interaction between ETV4 and METTL14 or m6A readers was confirmed by RIP assay and RNA pull-down assay. Animal experiments were performed to confirm METTL14 roles <em>in vivo</em>.</div></div><div><h3>Results</h3><div>METTL14 was downregulated in CRC tissues and cells, which overexpression inhibited proliferation and glycolysis, as well as promoted apoptosis and ferroptosis in CRC cells. METTL14 reduced the mRNA stability of ETV4 and inhibited ETV4 protein expression through m6A modification. m6A reader YTHDF2 could recognize m6A-methylated ETV4. The downregulation of ETV4 by METTL14 leads to increased apoptosis and ferroptosis in CRC cells, suggesting a critical role in tumor suppression. Moreover, METTL14 inhibited CRC tumorigenesis <em>in vivo</em> via reducing ETV4 expression.</div></div><div><h3>Conclusion</h3><div>METTL14 accelerated CRC cell apoptosis and ferroptosis via downregulating ETV4 in m6A-dependent manner, providing a molecular target for CRC treatment.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111910"},"PeriodicalIF":1.5,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144321574","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":"USP7 accelerates colorectal cancer progression by up-regulating MYO6 through deubiquitination","authors":"Ming Jiang ,&nbsp;Chong Xiong","doi":"10.1016/j.mrfmmm.2025.111908","DOIUrl":"10.1016/j.mrfmmm.2025.111908","url":null,"abstract":"<div><h3>Background</h3><div>Ubiquitin-specific protease 7 (USP7) is one of deubiquitinases and has been reported to regulate cancer cell biological processes through removing ubiquitin modifications from protein substrates. Myosins of class VI (MYO6) is shown to be highly expressed in many of cancers, and is associated with tumor progression in several cancers by affecting cell survival. Moreover, USP7 and MYO6 have been revealed to be involved in colorectal cancer (CRC) progression. Here, we aimed to investigate the intricate interplay between MYO6 and USP7 in CRC, and whether their interaction was associated with deubiquitination.</div></div><div><h3>Methods</h3><div>Quantitative real-time PCR and western blot were used to for mRNA and protein detection. Functional analyses were conducted using Cell Counting Kit-8, 5-ethynyl-2-deoxy-uridine, flow cytometry, wound healing and transwell assays in vitro, and murine xenograft models in vivo. M2 macrophage polarization was determined with CD206 antibody using flow cytometry. The protein interaction between MYO6 and USP7 was determined by chromatin immunoprecipitation assay. The deubiquitination effect of USP7 was validated by cellular ubiquitination and immunoprecipitation assay.</div></div><div><h3>Results</h3><div>CRC tissues and cells showed high expression of MYO6. Functionally, silencing of MYO6 suppressed CRC cell proliferation, migration, invasion, angiogenesis, induced cell apoptosis and negatively affected macrophage M2 polarization in vitro, and impeded CRC growth in vivo. For a mechanism analysis, USP7 could stabilize and up-regulate MYO6 expression by inducing MYO6 deubiquitination. USP7 was also highly expressed in CRC, USP7 silencing repressed CRC cell malignant phenotypes and reduced macrophage M2 polarization, while these effects were reversed by MYO6 overexpression.</div></div><div><h3>Conclusion</h3><div>MYO6 promoted CRC cell tumorigenesis and macrophage M2 polarization, and the mechanism was associated with USP7-induced MYO6 deubiquitination. These results suggested new targets for the development of epigenetic-based therapy in CRC.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111908"},"PeriodicalIF":1.5,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170526","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 report on five high-risk protein C pathogenic variants: G403R, P405S, S421N, C238S, and I243T","authors":"Daniela Hristov ,&nbsp;Done Stojanov","doi":"10.1016/j.mrfmmm.2025.111907","DOIUrl":"10.1016/j.mrfmmm.2025.111907","url":null,"abstract":"<div><div>In this study, we propose reclassification of 5 out of 16 <em>PROC</em> VUS (variants of uncertain significance): C238S, I243T, G403R, P405S, and S421N, as pathogenic variants, associated with thrombophilia due to <em>PROC</em> deficiency. The obtained results are based on in silico analysis, which enables a detailed assessment of variants’ impact, despite limited clinical evidence. In particular, the G403R substitution, next to the S402-active site, is expected to reduce the flexibility of the local coil domain, affecting the catalytic activity of serine protease. The P405S substitution may imply B-factor gain (P = 0.24; p-value=0.040). On the other hand, the S421N variant causes phosphorylation site disruption at S421, which serves as a target for CK2 phosphorylation. C238S substitution alters metal binding, while the I243T variant may alter transmembrane properties (P = 0.27, P-value=0.00071). All five <em>PROC</em> variants hold promise as diagnostic markers for protein C deficiency and may also serve as potential drug targets for therapeutic intervention.</div></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"831 ","pages":"Article 111907"},"PeriodicalIF":1.5,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144098887","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":"SIRT6 regulates the HIPK2/P53 pathway to reduce oxidative stress and apoptosis to attenuate vancomycin-induced nephrotoxicity","authors":"Xiuying Feng ,&nbsp;Yunhui Liu ,&nbsp;Lei Su ,&nbsp;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}