Pub Date : 2025-12-30DOI: 10.1016/j.gene.2025.149988
Chenlu Tang, Xiaofeng Jin
Endometrial cancer (EC) is one of the three most common malignancies of the female reproductive system, with its global incidence and disease-related mortality continuing to rise. Cervical cancer (CC), also known as uterine cervical cancer, refers to cancer occurring in the cervix. Despite the development of various therapeutic strategies, patient prognosis and survival rates remain poor due to high rates of metastasis and recurrence. Ubiquitination denotes the process by which ubiquitin is covalently attached to target proteins, while deubiquitinases (DUBs) catalyze the reverse process. Accumulating evidence indicates that dysregulation of deubiquitination plays significant roles in the pathogenesis and progression of both EC and CC. This review systematically summarizes recent research advances in DUBs, outlining their intrinsic characteristics, classification, catalytic mechanisms, and modes of activity regulation. Furthermore, it explores the potential mechanisms by which DUB dysregulation contributes to endometrial and cervical carcinogenesis. Additionally, we present the successful application of DUB inhibitors in the treatment of malignancies and provide an analysis of the current research status regarding targeted therapies for EC and CC.
{"title":"Deubiquitinating enzymes in endometrial cancer and cervical cancer","authors":"Chenlu Tang, Xiaofeng Jin","doi":"10.1016/j.gene.2025.149988","DOIUrl":"10.1016/j.gene.2025.149988","url":null,"abstract":"<div><div>Endometrial cancer (EC) is one of the three most common malignancies of the female reproductive system, with its global incidence and disease-related mortality continuing to rise. Cervical cancer (CC), also known as uterine cervical cancer, refers to cancer occurring in the cervix. Despite the development of various therapeutic strategies, patient prognosis and survival rates remain poor due to high rates of metastasis and recurrence. Ubiquitination denotes the process by which ubiquitin is covalently attached to target proteins, while deubiquitinases (DUBs) catalyze the reverse process. Accumulating evidence indicates that dysregulation of deubiquitination plays significant roles in the pathogenesis and progression of both EC and CC. This review systematically summarizes recent research advances in DUBs, outlining their intrinsic characteristics, classification, catalytic mechanisms, and modes of activity regulation. Furthermore, it explores the potential mechanisms by which DUB dysregulation contributes to endometrial and cervical carcinogenesis. Additionally, we present the successful application of DUB inhibitors in the treatment of malignancies and provide an analysis of the current research status regarding targeted therapies for EC and CC.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"983 ","pages":"Article 149988"},"PeriodicalIF":2.4,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-30DOI: 10.1016/j.gene.2025.149990
Qiyue Ma , Ningna Wang , Kaikai Qiao , Kun Luo , Chenglong Zhao , Jiaxuan Yan , Shuli Fan , Junkang Rong , Qifeng Ma
Male reproductive development is fundamental to the life cycle of flowering plants, culminating in seed production. Aberrations in anther development frequently lead to male sterility, yet the underlying molecular mechanisms in upland cotton (Gossypium hirsutum) remain largely uncharacterized. The R2R3-MYB family of transcription factors are known key regulators of diverse developmental processes, including male fertility in several model species. Here, we identify and functionally characterize GhMYB35, an R2R3-MYB transcription factor that plays an essential role in cotton anther development. CRISPR/Cas9-mediated knockout of GhMYB35 resulted in complete male sterility, with mutants (ghmyb35) exhibiting indehiscent anthers, shorter filaments, and a total absence of viable pollen. Expression analyses reveal that GhMYB35 is predominantly expressed in anthers, with peak expression of its A- and D-subgenome homoeologs occurring at developmental stage 7. Subcellular localization results show that both GhMYB35_A and GhMYB35_D are nuclear-localized transcription factors. Furthermore, the total absence of GhMYB35 leads to pollen abortion and subsequent anther collapse without dehiscence. Collectively, our findings establish GhMYB35 as a critical regulator of anther maturation, thereby elucidating a key component of the molecular network governing male fertility in cotton.
{"title":"The R2R3-MYB transcription factor GhMYB35 governs anther development and pollen viability in upland cotton","authors":"Qiyue Ma , Ningna Wang , Kaikai Qiao , Kun Luo , Chenglong Zhao , Jiaxuan Yan , Shuli Fan , Junkang Rong , Qifeng Ma","doi":"10.1016/j.gene.2025.149990","DOIUrl":"10.1016/j.gene.2025.149990","url":null,"abstract":"<div><div>Male reproductive development is fundamental to the life cycle of flowering plants, culminating in seed production. Aberrations in anther development frequently lead to male sterility, yet the underlying molecular mechanisms in upland cotton (<em>Gossypium hirsutum</em>) remain largely uncharacterized. The R2R3-MYB family of transcription factors are known key regulators of diverse developmental processes, including male fertility in several model species. Here, we identify and functionally characterize <em>GhMYB35</em>, an R2R3-MYB transcription factor that plays an essential role in cotton anther development. CRISPR/Cas9-mediated knockout of <em>GhMYB35</em> resulted in complete male sterility, with mutants (<em>ghmyb35</em>) exhibiting indehiscent anthers, shorter filaments, and a total absence of viable pollen. Expression analyses reveal that <em>GhMYB35</em> is predominantly expressed in anthers, with peak expression of its A- and D-subgenome homoeologs occurring at developmental stage 7. Subcellular localization results show that both<!--> <em>GhMYB35_A</em> <!-->and<!--> <em>GhMYB35_D</em> <!-->are nuclear-localized transcription factors. Furthermore, the total absence of GhMYB35 leads to pollen abortion and subsequent anther collapse without dehiscence. Collectively, our findings establish <em>GhMYB35</em> as a critical regulator of anther maturation, thereby elucidating a key component of the molecular network governing male fertility in cotton.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"984 ","pages":"Article 149990"},"PeriodicalIF":2.4,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The contribution of low-penetrance DNA repair genes (DRGs) to ovarian cancer (OC) risk remains poorly understood. Variants in homologous recombination repair (HRR) and non-homologous end joining (NHEJ) pathway genes may influence genomic stability and modulate OC susceptibility. This population-based case–control study (474 subjects; 237 OC patients and 237 controls) evaluated polymorphisms in RAD51, XRCC2, XRCC3 (HRR), and XRCC4, LIG4 (NHEJ) to assess their role in OC predisposition. Genotyping was performed using PCR-RFLP, and logistic regression estimated risk associations. Multifactor Dimensionality Reduction (MDR) analysis examined SNP–SNP interactions, while in silico tools and electrostatic surface mapping predicted structural and functional effects. Significant associations were observed for RAD51 (rs1801320), where individuals with the mutant CC genotype showed a 2.8-fold higher OC risk (OR = 2.85; 95 % CI = 1.15–7.06; p = 0.049), and the CT genotype of LIG4 (rs1805388) conferred a 1.85-fold increased risk (OR = 1.85; 95 % CI = 1.11–3.07; p = 0.0097). Conversely, CT genotype carriers of XRCC3 (rs861539) exhibited reduced OC risk (OR = 0.49; 95 % CI = 0.32–0.75; p = 0.003). XRCC2 and XRCC4 showed no significant associations. However, XRCC2 variants correlated with tumor grade and menopausal status, and XRCC3 with tumor histology. MDR analysis revealed strong interactions between XRCC3 and RAD51, followed by combinations involving XRCC2, suggesting synergistic HRR gene effects. In silico predictions indicated XRCC2 R188H is destabilizing, XRCC3 T241M has mixed effects, and LIG4 T9I is stabilizing. Overall, RAD51 and LIG4 polymorphisms may contribute to OC susceptibility in South Indian women. Larger, multi-center studies are warranted to validate these findings and explore their potential as predictive biomarkers for OC.
低外显率DNA修复基因（DRGs）对卵巢癌（OC）风险的贡献仍然知之甚少。同源重组修复（HRR）和非同源末端连接（NHEJ）途径基因的变异可能影响基因组稳定性并调节OC易感性。这项基于人群的病例对照研究（474名受试者，237名OC患者和237名对照）评估了RAD51、XRCC2、XRCC3 （HRR）和XRCC4、LIG4 （NHEJ）的多态性，以评估它们在OC易感性中的作用。使用PCR-RFLP进行基因分型，并进行logistic回归估计风险关联。多因素降维（MDR）分析检查了SNP-SNP相互作用，而在硅工具和静电表面作图预测了结构和功能效应。在RAD51 （rs1801320）中观察到显著的相关性，其中突变CC基因型个体的OC风险增加2.8倍（OR = 2.85; 95% CI = 1.15-7.06; p = 0.049），而CT基因型LIG4 （rs1805388）的风险增加1.85倍（OR = 1.85; 95% CI = 1.11-3.07; p = 0.0097）。相反，CT基因型携带者XRCC3 （rs861539）表现出较低的OC风险（OR = 0.49; 95% CI = 0.32-0.75; p = 0.003）。XRCC2和XRCC4无显著相关性。然而，XRCC2变异与肿瘤分级和绝经状态相关，XRCC3与肿瘤组织学相关。MDR分析显示，XRCC3与RAD51之间存在较强的相互作用，其次是涉及XRCC2的组合，提示HRR基因的协同作用。计算机预测表明，XRCC2 R188H具有不稳定性，XRCC3 T241M具有混合效应，而LIG4 T9I具有稳定性。总的来说，RAD51和LIG4多态性可能与南印度妇女的OC易感性有关。需要更大规模、多中心的研究来验证这些发现，并探索其作为卵巢癌预测生物标志物的潜力。
{"title":"Integrated case–control and in silico analysis of DNA double-strand break repair gene variants (RAD51, XRCC2, XRCC3, XRCC4, and LIG4) for ovarian cancer susceptibility","authors":"Harshavardhani Canchi Sistla , Arun Seshachalam , Krishna Kumar Rathnam , Taruna Rajagopal , Srikanth Talluri , Subaranjana Saravanaguru Vasanthi , Nageswara Rao Dunna","doi":"10.1016/j.gene.2025.149989","DOIUrl":"10.1016/j.gene.2025.149989","url":null,"abstract":"<div><div>The contribution of low-penetrance DNA repair genes (DRGs) to ovarian cancer (OC) risk remains poorly understood. Variants in homologous recombination repair (HRR) and non-homologous end joining (NHEJ) pathway genes may influence genomic stability and modulate OC susceptibility. This population-based case–control study (474 subjects; 237 OC patients and 237 controls) evaluated polymorphisms in <em>RAD51, XRCC2, XRCC3</em> (HRR), and <em>XRCC4, LIG4</em> (NHEJ) to assess their role in OC predisposition. Genotyping was performed using PCR-RFLP, and logistic regression estimated risk associations. Multifactor Dimensionality Reduction (MDR) analysis examined SNP–SNP interactions, while <em>in silico</em> tools and electrostatic surface mapping predicted structural and functional effects. Significant associations were observed for <em>RAD51</em> (rs1801320), where individuals with the mutant CC genotype showed a 2.8-fold higher OC risk (OR = 2.85; 95 % CI = 1.15–7.06; p = 0.049), and the CT genotype of <em>LIG4</em> (rs1805388) conferred a 1.85-fold increased risk (OR = 1.85; 95 % CI = 1.11–3.07; p = 0.0097). Conversely, CT genotype carriers of <em>XRCC3</em> (rs861539) exhibited reduced OC risk (OR = 0.49; 95 % CI = 0.32–0.75; p = 0.003). <em>XRCC2</em> and <em>XRCC4</em> showed no significant associations. However, <em>XRCC2</em> variants correlated with tumor grade and menopausal status, and <em>XRCC3</em> with tumor histology. MDR analysis revealed strong interactions between <em>XRCC3</em> and <em>RAD51</em>, followed by combinations involving <em>XRCC2</em>, suggesting synergistic HRR gene effects. <em>In silico</em> predictions indicated XRCC2 R188H is destabilizing, XRCC3 T241M has mixed effects, and LIG4 T9I is stabilizing. Overall, <em>RAD51</em> and <em>LIG4</em> polymorphisms may contribute to OC susceptibility in South Indian women. Larger, multi-center studies are warranted to validate these findings and explore their potential as predictive biomarkers for OC.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"983 ","pages":"Article 149989"},"PeriodicalIF":2.4,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145882812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The DOT1L gene encodes a histone lysine methyltransferase that has the distinctive characteristic of being composed of a DOT1 catalytic domain that targets lysine 79 of the core globular domain of histone H3. DOT1L missense variants have recently been implicated in an autosomal dominant inheritance syndrome with developmental delay and congenital anomalies in postnatal cohorts. We report the twenty-sixth patient with this disorder.
Methods
Trio genome sequencing (GS) was performed in a patient with developmental delay.
Results
Clinical examination showed a predominant global developmental delay affecting language, with cerebral abnormalities visible on magnetic resonance imaging, hypotonia, and ophthalmological and musculoskeletal abnormalities. GS revealed a de novo heterozygous missense variant in exon 3 of DOT1L (c.161C > T; p.(Ala54Val)), which is reported for the first time as the cause of developmental delay and congenital anomalies.
Discussion
Among the 26 reported patients, 23 have missense variants, two have truncating variants, and one has an in-frame deletion. The mode of transmission is predominantly de novo. Current studies indicate multiple pathogenic mechanisms underlying DOT1L-related disorder, including both gain-of-function and loss-of-function effects, underscoring the complexity of the disease etiology. Although the gene exhibits intolerance to loss-of-function variants, a considerable number of truncating variants are observed in control populations, suggesting incomplete penetrance and heterogeneity in the phenotypic expression of DOT1L-associated disorder. No phenotype-genotype correlation could be established. Among reported patients, including ours, the most consistent clinical manifestations are global developmental delay, predominantly affecting language and behavior, and possibly distinctive facial features.
{"title":"Case report and literature review of neurodevelopmental syndrome linked to DOT1L variants","authors":"Aurélien Caux , Florence Jobic , Boris Keren , Alexis Billes , Virginie Magry , Anaïs L’Haridon , Walaa Darwiche , Guillaume Jedraszak , Gilles Morin","doi":"10.1016/j.gene.2025.149987","DOIUrl":"10.1016/j.gene.2025.149987","url":null,"abstract":"<div><h3>Introduction</h3><div>The <em>DOT1L</em> gene encodes a histone lysine methyltransferase that has the distinctive characteristic of being composed of a DOT1 catalytic domain that targets lysine 79 of the core globular domain of histone H3. <em>DOT1L</em> missense variants have recently been implicated in an autosomal dominant inheritance syndrome with developmental delay and congenital anomalies in postnatal cohorts. We report the twenty-sixth patient with this disorder.</div></div><div><h3>Methods</h3><div>Trio genome sequencing (GS) was performed in a patient with developmental delay.</div></div><div><h3>Results</h3><div>Clinical examination showed a predominant global developmental delay affecting language, with cerebral abnormalities visible on magnetic resonance imaging, hypotonia, and ophthalmological and musculoskeletal abnormalities. GS revealed a <em>de novo</em> heterozygous missense variant in exon 3 of <em>DOT1L</em> (c.161C > T; p.(Ala54Val)), which is reported for the first time as the cause of developmental delay and congenital anomalies.</div></div><div><h3>Discussion</h3><div>Among the 26 reported patients, 23 have missense variants, two have truncating variants, and one has an in-frame deletion. The mode of transmission is predominantly <em>de novo</em>. Current studies indicate multiple pathogenic mechanisms underlying DOT1L-related disorder, including both gain-of-function and loss-of-function effects, underscoring the complexity of the disease etiology. Although the gene exhibits intolerance to loss-of-function variants, a considerable number of truncating variants are observed in control populations, suggesting incomplete penetrance and heterogeneity in the phenotypic expression of DOT1L-associated disorder. No phenotype-genotype correlation could be established. Among reported patients, including ours, the most consistent clinical manifestations are global developmental delay, predominantly affecting language and behavior, and possibly distinctive facial features.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"983 ","pages":"Article 149987"},"PeriodicalIF":2.4,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145870010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-24DOI: 10.1016/j.gene.2025.149985
Shengting Zhang , Sha Zhao , Lijuan Liu , Huili Tao , Jinmei Chai , Yani Ju , Chengqian Dong , Yunlin Wei
Enterococcus faecalis is a facultative anaerobe often associated with persistent infections. It can rapidly adapt and grow in environments with varying oxygen levels (aerobic, microaerobic, hypoxic, and anaerobic), making it a major pathogen responsible for refractory periapical periodontitis. The study investigated the fatty acid content and its variations in Enterococcus faecalis strain YN771 under different oxygen concentrations. Subsequently, transcriptomics and metabolomics were combined to characterize the underlying mechanisms. The results showed that YN771 exhibited altered transcriptional and metabolomic profiles when exposed to different oxygen levels. These changes highlighted the oxygen adaptation and regulatory mechanisms of YN771, including sulfur metabolism, glutathione metabolism, glutamate metabolism, pyruvate metabolism, tricarboxylic acid cycle, peptidoglycan biosynthesis, and fatty acid biosynthesis regulation. Additionally, the study examined the expression changes of virulence factors in YN771 under different oxygen levels, which are also regulated by quorum sensing. This research comprehensively explores the metabolic regulation of YN771 under varying oxygen levels and analyzes key enzyme genes and virulence factors involved in its oxygen response regulation, providing mechanistic insights for developing therapeutic strategies against this notorious pathogen.
{"title":"Transcriptomic and metabolomic insights into the oxygen adaptation mechanisms of Enterococcus faecalis YN771","authors":"Shengting Zhang , Sha Zhao , Lijuan Liu , Huili Tao , Jinmei Chai , Yani Ju , Chengqian Dong , Yunlin Wei","doi":"10.1016/j.gene.2025.149985","DOIUrl":"10.1016/j.gene.2025.149985","url":null,"abstract":"<div><div><em>Enterococcus faecalis</em> is a facultative anaerobe often associated with persistent infections. It can rapidly adapt and grow in environments with varying oxygen levels (aerobic, microaerobic, hypoxic, and anaerobic), making it a major pathogen responsible for refractory periapical periodontitis. The study investigated the fatty acid content and its variations in <em>Enterococcus faecalis</em> strain YN771 under different oxygen concentrations. Subsequently, transcriptomics and metabolomics were combined to characterize the underlying mechanisms. The results showed that YN771 exhibited altered transcriptional and metabolomic profiles when exposed to different oxygen levels. These changes highlighted the oxygen adaptation and regulatory mechanisms of YN771, including sulfur metabolism, glutathione metabolism, glutamate metabolism, pyruvate metabolism, tricarboxylic acid cycle, peptidoglycan biosynthesis, and fatty acid biosynthesis regulation. Additionally, the study examined the expression changes of virulence factors in YN771 under different oxygen levels, which are also regulated by quorum sensing. This research comprehensively explores the metabolic regulation of YN771 under varying oxygen levels and analyzes key enzyme genes and virulence factors involved in its oxygen response regulation, providing mechanistic insights for developing therapeutic strategies against this notorious pathogen.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"982 ","pages":"Article 149985"},"PeriodicalIF":2.4,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145839022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-24DOI: 10.1016/j.gene.2025.149986
Ze Yao , Ming Lu , Chunshuang Li , Xiang Li , Hui Shang , Songtao Bie
Ginsenoside Rg1 (Rg1), an active compound in Panax ginseng C. A. Meyer (ginseng), has shown potential to ameliorate age-related cell damage and extend lifespan in multiple model organisms. However, the precise molecular mechanisms of its anti-aging effects remain unclear. In this study, we explore the anti-aging mechanisms of ginsenoside Rg1, focusing on its impact on mitophagy in Saccharomyces cerevisiae. Using propidium iodide staining, we found that Rg1 extends the chronological lifespan (CLS) of yeast cells. Further analyses revealed that Rg1 enhances mitochondrial function and antioxidant capacity in yeast cells by inducing mitophagy. Moreover, RNA-Seq and bioinformatics analyses identified the molecular chaperone SSE1 as a key target of Rg1. SSE1 knockout strain demonstrated that Rg1 enhances mitochondrial function and antioxidant capacity through SSE1-dependent mitophagy, thereby extending cell lifespan. Collectively, we concluded that Rg1 exerts its anti-aging effects through SSE1-mediated mitophagy. This study advances our understanding of Rg1-mediated mitophagy and mitochondrial regulation via SSE1, offering a foundation for the rational design of targeted anti-aging treatments.
{"title":"Ginsenoside Rg1 delays chronological aging in a yeast model via SSE1-Mediated mitophagy","authors":"Ze Yao , Ming Lu , Chunshuang Li , Xiang Li , Hui Shang , Songtao Bie","doi":"10.1016/j.gene.2025.149986","DOIUrl":"10.1016/j.gene.2025.149986","url":null,"abstract":"<div><div>Ginsenoside Rg1 (Rg1), an active compound in <em>Panax ginseng</em> C. A. Meyer (ginseng), has shown potential to ameliorate age-related cell damage and extend lifespan in multiple model organisms. However, the precise molecular mechanisms of its anti-aging effects remain unclear. In this study, we explore the anti-aging mechanisms of ginsenoside Rg1, focusing on its impact on mitophagy in <em>Saccharomyces cerevisiae</em>. Using propidium iodide staining, we found that Rg1 extends the chronological lifespan (CLS) of yeast cells. Further analyses revealed that Rg1 enhances mitochondrial function and antioxidant capacity in yeast cells by inducing mitophagy. Moreover, RNA-Seq and bioinformatics analyses identified the molecular chaperone <em>SSE1</em> as a key target of Rg1. <em>SSE1</em> knockout strain demonstrated that Rg1 enhances mitochondrial function and antioxidant capacity through <em>SSE1</em>-dependent mitophagy, thereby extending cell lifespan. Collectively, we concluded that Rg1 exerts its anti-aging effects through <em>SSE1</em>-mediated mitophagy. This study advances our understanding of Rg1-mediated mitophagy and mitochondrial regulation via <em>SSE1</em>, offering a foundation for the rational design of targeted anti-aging treatments.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"982 ","pages":"Article 149986"},"PeriodicalIF":2.4,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145839702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-23DOI: 10.1016/j.gene.2025.149970
Ju Tang , Ying-Feng Hu , Jian-Wen Shao , Zhi-Zhong Li
Phoebe chekiangensis, a nationally protected tree endemic to southeastern China, is of high ecological and economic value but lacks genomic resources for conservation and evolutionary studies. In this study, we assembled its complete organelle genomes, including a circular mitogenome of 864,971 bp and a plastome of 154,460 bp. The mitogenome is enriched in dispersed and simple sequence repeats, consistent with extensive structural rearrangements across Lauraceae, whereas coding regions (over 80 % similarity) remain largely collinear under strong functional constraints. We identified 31 mitochondrial plastid DNA sequences (26,890 bp; 3.11 % of the mitogenome), including five intact plastid protein-coding genes (PCGs) and 14 tRNAs, reflecting frequent plastid-to-mitochondrion transfers that may restore missing tRNAs and enhance genome variability. RNA editing analysis revealed 71 mitochondrial and 13 plastid sites, with cox1 harboring the most, suggesting post-transcriptional modification of respiratory genes that could contribute to stress tolerance. Comparative analyses showed that plastid PCGs evolve faster than mitochondrial PCGs, and atp6 displayed a signal of positive selection, potentially linked to adaptive adjustments in ATP synthase function and respiratory efficiency. Phylogenetic analyses based on organelle genomes confirmed the monophyly of Lauraceae but revealed little topological conflicts, likely reflecting lineage-specific substitution-rate heterogeneity. In conclusion, our results provide new insights into the dynamics of organelle genome evolution and establish valuable genomic resources for the conservation and molecular systematics of P. chekiangensis and Lauraceae.
{"title":"Organelle genome analysis reveals adaptation and conservation in endangered tree Phoebe chekiangensis","authors":"Ju Tang , Ying-Feng Hu , Jian-Wen Shao , Zhi-Zhong Li","doi":"10.1016/j.gene.2025.149970","DOIUrl":"10.1016/j.gene.2025.149970","url":null,"abstract":"<div><div><em>Phoebe chekiangensis</em>, a nationally protected tree endemic to southeastern China, is of high ecological and economic value but lacks genomic resources for conservation and evolutionary studies. In this study, we assembled its complete organelle genomes, including a circular mitogenome of 864,971 bp and a plastome of 154,460 bp. The mitogenome is enriched in dispersed and simple sequence repeats, consistent with extensive structural rearrangements across Lauraceae, whereas coding regions (over 80 % similarity) remain largely collinear under strong functional constraints. We identified 31 mitochondrial plastid DNA sequences (26,890 bp; 3.11 % of the mitogenome), including five intact plastid protein-coding genes (PCGs) and 14 tRNAs, reflecting frequent plastid-to-mitochondrion transfers that may restore missing tRNAs and enhance genome variability. RNA editing analysis revealed 71 mitochondrial and 13 plastid sites, with <em>cox1</em> harboring the most, suggesting post-transcriptional modification of respiratory genes that could contribute to stress tolerance. Comparative analyses showed that plastid PCGs evolve faster than mitochondrial PCGs, and <em>atp6</em> displayed a signal of positive selection, potentially linked to adaptive adjustments in ATP synthase function and respiratory efficiency. Phylogenetic analyses based on organelle genomes confirmed the monophyly of Lauraceae but revealed little topological conflicts, likely reflecting lineage-specific substitution-rate heterogeneity. In conclusion, our results provide new insights into the dynamics of organelle genome evolution and establish valuable genomic resources for the conservation and molecular systematics of <em>P. chekiangensis</em> and Lauraceae.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"982 ","pages":"Article 149970"},"PeriodicalIF":2.4,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145832854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-23DOI: 10.1016/j.gene.2025.149978
Qingqing Wei , Wenhui Li , Guina Cui , Yiliang Xu , Shaorong Gao
Bovine induced pluripotent stem cells (biPSCs), which can be obtained through somatic cells reprogramming have multiple potential applications in human disease, regeneration medicine and biotechnical animal breeding. However, the low reprogramming efficiency and poorly exploration of the mechanism underlying the somatic cells reprogramming in cattle restricted the applications of biPSCs. Here, we reported the transcription factor PR-domain containing protein 14 (PRDM14) was highly expressed in bovine fetal testis and intestine. And the expression of PRDM14 showed the lowest level in bovine embryonic fibroblasts (BEF), increased on day 3 and day 18, and finally reached the highest level in induced pluripotent stem cells (iPSCs) during the reprogramming induced by OCT4, SOX2, KLF4 and MYC (OSKM). In a gain-of-function assay, we showed that PRDM14 was able to enhance the efficiency of reprogramming from BEF in conjunction with bovine OSKM. While, silencing of PRDM14 inhibited the reprogramming efficiency of BEF. The bovine iPSCs derived from OSKM plus PRDM14 displayed normal karyotype, expressed pluripotent markers and could differentiated into three germ layers in vitro. Transcriptome analysis of cells at the early, median and late reprogramming stages revealed that several genes involved in oxidative phosphorylation (OXPHOS) are upregulated on day 3 when OXPHOS burst occurs, while downregulated on day 15 when OXPHOS transmits to glycolysis, by ectopic expression of PRDM14. RT-qPCR and ATP content detection further confirmed that PRDM14 could improve somatic cells reprogramming by enhancing OXPHOS at the early stage. Additionally, forced expression of PRDM14 in OSKM-induced biPSCs showed that it upregulates the expression of key pluripotency gene NANOG but downregulates LIN28, DNA methylation genes DNMT1/3B and DNA demethylation genes TET1/2/3. Altogether, our study uncovers PRDM14 exemplifies a key transcription factor required for the reacquisition of pluripotency in bovine somatic cells and the maintenance of bovine iPSCs identity.
{"title":"PRDM14 promotes the bovine somatic stem cell reprogramming through enhancing oxidative phosphorylation at the initial stage","authors":"Qingqing Wei , Wenhui Li , Guina Cui , Yiliang Xu , Shaorong Gao","doi":"10.1016/j.gene.2025.149978","DOIUrl":"10.1016/j.gene.2025.149978","url":null,"abstract":"<div><div>Bovine induced pluripotent stem cells (biPSCs), which can be obtained through somatic cells reprogramming have multiple potential applications in human disease, regeneration medicine and biotechnical animal breeding. However, the low reprogramming efficiency and poorly exploration of the mechanism underlying the somatic cells reprogramming in cattle restricted the applications of biPSCs. Here, we reported the transcription factor PR-domain containing protein 14 (<em>PRDM14</em>) was highly expressed in bovine fetal testis and intestine. And the expression of <em>PRDM14</em> showed the lowest level in bovine embryonic fibroblasts (BEF), increased on day 3 and day 18, and finally reached the highest level in induced pluripotent stem cells (iPSCs) during the reprogramming induced by <em>OCT4</em>, <em>SOX2</em>, <em>KLF4</em> and <em>MYC</em> (OSKM). In a gain-of-function assay, we showed that <em>PRDM14</em> was able to enhance the efficiency of reprogramming from BEF in conjunction with bovine OSKM. While, silencing of <em>PRDM14</em> inhibited the reprogramming efficiency of BEF. The bovine iPSCs derived from OSKM plus <em>PRDM14</em> displayed normal karyotype, expressed pluripotent markers and could differentiated into three germ layers in vitro. Transcriptome analysis of cells at the early, median and late reprogramming stages revealed that several genes involved in oxidative phosphorylation (OXPHOS) are upregulated on day 3 when OXPHOS burst occurs, while downregulated on day 15 when OXPHOS transmits to glycolysis, by ectopic expression of <em>PRDM14</em>. RT-qPCR and ATP content detection further confirmed that <em>PRDM14</em> could improve somatic cells reprogramming by enhancing OXPHOS at the early stage. Additionally, forced expression of <em>PRDM14</em> in OSKM-induced biPSCs showed that it upregulates the expression of key pluripotency gene <em>NANOG</em> but downregulates <em>LIN28</em>, DNA methylation genes <em>DNMT1</em>/<em>3B</em> and DNA demethylation genes <em>TET1</em>/<em>2</em>/<em>3</em>. Altogether, our study uncovers <em>PRDM14</em> exemplifies a key transcription factor required for the reacquisition of pluripotency in bovine somatic cells and the maintenance of bovine iPSCs identity.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"982 ","pages":"Article 149978"},"PeriodicalIF":2.4,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1016/j.gene.2025.149945
Seyedeh Zahra Mousavi , Masomeh Askari , Ken McElreavey , Anu Bashamboo , Najmeh Salehi , Mandana Rastari , Zeynab Rokhsattalab , Bahram Mohammad Soltani , Mehdi Totonchi
Introduction
Teratozoospermia, characterized by abnormal sperm morphology, is a significant factor contributing to the male infertility. Deubiquitinating enzymes play a crucial role in controlling protein synthesis and degradation during spermatogenesis.
Methods
Whole exome sequencing (WES) and the following insilico analysis were performed to detect the associated variant with asthenoteratozoospermia in a consanguineous Iranian family with two affected brothers.
Results
WES identified a novel candidate hemizygous missense mutation (chrX-132161044 T > G:NM_031907.2:c.1205A > C, p.Asn402Thr) in the catalytic domain of the USP26 (Ubiquitin-Specific Peptidase 26) deubiquitinating enzyme in two affected siblings. The USP26 encodes a testis-specific deubiquitinating enzyme which is necessary for normal spermatogenesis and may influence male fertility. The mutation changes asparagine 402 (N) into threonine (T) and was co-segregated with phenotype in other available family members. In-silico predictions indicate that the N402T change not only leads to the absence of a hydrogen bond between the mutant N402T and F430 residues but also causes a reduction in USP26 protein stability, potentially resulting in defects in USP26 enzymatic activity.
Conclusions
Our findings support a potential role for USP26 variants contributing to asthenoteratozoospermia.
摘要畸形精子症是导致男性不育的重要因素，其特征是精子形态异常。去泛素化酶在控制精子发生过程中蛋白质的合成和降解中起着至关重要的作用。方法：采用全外显子组测序（WES）和以下计算机分析方法检测一个有两个兄弟患病的伊朗近亲家庭中与弱异卵精子症相关的变异。结果：WES鉴定出一种新的候选半合子错义突变（chrX-132161044 T > G:NM_031907.2:c）。1205A > C, p.Asn402Thr)在两个患病兄弟姐妹的USP26（泛素特异性肽酶26）去泛素化酶的催化区域。USP26编码睾丸特异性去泛素化酶，这是正常精子发生所必需的，并可能影响男性生育能力。该突变将天冬酰胺402 (N)转变为苏氨酸(T)，并与其他可用家族成员的表型共分离。硅预测表明，N402T的变化不仅导致突变体N402T和F430残基之间缺乏氢键，而且还导致USP26蛋白稳定性降低，可能导致USP26酶活性缺陷。结论：我们的研究结果支持USP26变异对弱异卵精子症的潜在作用。
{"title":"A novel candidate missense variant in the catalytic domain of USP26 associated with asthenoteratozoospermia","authors":"Seyedeh Zahra Mousavi , Masomeh Askari , Ken McElreavey , Anu Bashamboo , Najmeh Salehi , Mandana Rastari , Zeynab Rokhsattalab , Bahram Mohammad Soltani , Mehdi Totonchi","doi":"10.1016/j.gene.2025.149945","DOIUrl":"10.1016/j.gene.2025.149945","url":null,"abstract":"<div><h3>Introduction</h3><div>Teratozoospermia, characterized by abnormal sperm morphology, is a significant factor contributing to the male infertility. Deubiquitinating enzymes play a crucial role in controlling protein synthesis and degradation during spermatogenesis.</div></div><div><h3>Methods</h3><div>Whole exome sequencing (WES) and the following insilico analysis were performed to detect the associated variant with asthenoteratozoospermia in a consanguineous Iranian family with two affected brothers.</div></div><div><h3>Results</h3><div>WES identified a novel candidate hemizygous missense mutation (chrX-132161044 T > G:NM_031907.2:c.1205A > C, p.Asn402Thr) in the catalytic domain of the <em>USP26</em> (Ubiquitin-Specific Peptidase 26) deubiquitinating enzyme in two affected siblings. The <em>USP26</em> encodes a testis-specific deubiquitinating enzyme which is necessary for normal spermatogenesis and may influence male fertility. The mutation changes asparagine 402 (N) into threonine (T) and was co-segregated with phenotype in other available family members. In-silico predictions indicate that the N402T change not only leads to the absence of <em>a</em> hydrogen bond between the mutant N402T and F430 residues but also causes a reduction in <em>USP26</em> protein stability, potentially resulting in defects in <em>USP26</em> enzymatic activity.</div></div><div><h3>Conclusions</h3><div>Our findings support a potential role for <em>USP26</em> variants contributing to asthenoteratozoospermia.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"982 ","pages":"Article 149945"},"PeriodicalIF":2.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1016/j.gene.2025.149969
Xinyang Li , Chong Liu , Haidi Hu
Furin is a calcium-dependent serine endoprotease that activates multiple substrates by cleaving at polybasic motifs, playing a pivotal role in human physiology and pathology. This review summarizes the latest research progress regarding Furin’s extensive involvement in infectious diseases, tumor diseases, cardiovascular diseases, neurodegenerative diseases, metabolic diseases, and autoimmune diseases. This review offers an in-depth analysis of Furin’s dual functions, which include promoting viral entry into host cells, driving oncogenesis via growth factors, metalloproteinases, and the Notch signaling pathway, and maintaining metabolic homeostasis and immune tolerance. Key pathophysiological mechanisms involve the dysfunction of Furin substrate activation in atherosclerosis, hypertension, Alzheimer’s disease, diabetes, and other disorders. The review also highlights the potential value of Furin as a diagnostic and prognostic biomarker and therapeutic target, while pointing out the challenges encountered in developing its inhibitors.
{"title":"The expanding role of Furin in human Disease: A comprehensive review","authors":"Xinyang Li , Chong Liu , Haidi Hu","doi":"10.1016/j.gene.2025.149969","DOIUrl":"10.1016/j.gene.2025.149969","url":null,"abstract":"<div><div>Furin is a calcium-dependent serine endoprotease that activates multiple substrates by cleaving at polybasic motifs, playing a pivotal role in human physiology and pathology. This review summarizes the latest research progress regarding Furin’s extensive involvement in infectious diseases, tumor diseases, cardiovascular diseases, neurodegenerative diseases, metabolic diseases, and autoimmune diseases. This review offers an in-depth analysis of Furin’s dual functions, which include promoting viral entry into host cells, driving oncogenesis via growth factors, metalloproteinases, and the Notch signaling pathway, and maintaining metabolic homeostasis and immune tolerance. Key pathophysiological mechanisms involve the dysfunction of Furin substrate activation in atherosclerosis, hypertension, Alzheimer’s disease, diabetes, and other disorders. The review also highlights the potential value of Furin as a diagnostic and prognostic biomarker and therapeutic target, while pointing out the challenges encountered in developing its inhibitors.</div></div>","PeriodicalId":12499,"journal":{"name":"Gene","volume":"981 ","pages":"Article 149969"},"PeriodicalIF":2.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145804006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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