Nucleic Acids Research最新文献_第8页

Inhibition of DNA cleavage and strand passage activities of Mycobacterium tuberculosis topoisomerase I 结核分枝杆菌拓扑异构酶I对DNA切割和链传递活性的抑制作用

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-09-20 DOI: 10.1093/nar/gkaf929

Iqball Faheem, Majety Naga Leelaram, Immadi Siva Ratnakar, Rinkee Verma, Valakunja Nagaraja

{"title":"Inhibition of DNA cleavage and strand passage activities of Mycobacterium tuberculosis topoisomerase I","authors":"Iqball Faheem, Majety Naga Leelaram, Immadi Siva Ratnakar, Rinkee Verma, Valakunja Nagaraja","doi":"10.1093/nar/gkaf929","DOIUrl":"https://doi.org/10.1093/nar/gkaf929","url":null,"abstract":"Topoisomerase I (TopoI) is the sole DNA relaxase in Mycobacterium tuberculosis. Despite being a validated drug target and indispensable to the pathogen, only a limited repertoire of inhibitors targeting the enzyme have been identified. We employed monoclonal antibodies (mAbs) to address this shortfall. From the pool of a large number of mAbs, we describe an inhibitory mAb specific to mycobacterial TopoI with a distinct mechanism of action. Among the various steps of the TopoI reaction cycle, the mAb does not interfere with DNA binding but impedes DNA cleavage. It does not alter the religation activity of TopoI; however, it inhibits its strand passage activity. Probing with the mAb, we show the precise step at which the topology of the DNA is changed during DNA relaxation reaction. Surprisingly, instead of the initial strand scission action of the enzyme, the subsequent strand passage followed by the second transesterification entails the alteration in DNA topology. With their selective and specific inhibitory properties, the mAb and its derived single-chain variable fragment (ScFv) would serve to probe the structure of mycobacterial TopoI and as a starting point in designing peptide inhibitors with therapeutic potential to combat the rampant drug-resistant M. tuberculosis.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"39 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Control of the archaeal DNA damage-responsive pathway by phosphorylation of Orc1-2, the global regulator in Saccharolobus islandicus 岛糖酵母（Saccharolobus islandicus）全局调控基因Orc1-2磷酸化对古细菌DNA损伤响应通路的控制

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-09-20 DOI: 10.1093/nar/gkaf927

Xiaotong Liu, Xu Feng, Guanhua Yuan, Fang Wang, Qihong Huang, Jianan Xu, Yulong Shen, Qunxin She

{"title":"Control of the archaeal DNA damage-responsive pathway by phosphorylation of Orc1-2, the global regulator in Saccharolobus islandicus","authors":"Xiaotong Liu, Xu Feng, Guanhua Yuan, Fang Wang, Qihong Huang, Jianan Xu, Yulong Shen, Qunxin She","doi":"10.1093/nar/gkaf927","DOIUrl":"https://doi.org/10.1093/nar/gkaf927","url":null,"abstract":"Archaea employ Orc1-2, an Orc1/Cdc6 family protein, to mediate DNA damage-responsive (DDR) regulation, which orchestrates a series of cellular responses to DNA damage. However, how the DDR process is regulated remains elusive. To investigate whether the Orc1-2 functions could be regulated by posttranslational modifications (PTMs), differential PTMs were analyzed for Orc1-2 proteins in cells of normal growth versus those in DNA damage-treated cells. We found only Orc1-2 proteins present in untreated cells are phosphorylated at T356. Since T356 is located in the DNA-binding pocket of the archaeal DDR regulator in the predicted structure, its phosphorylation may impair the DNA binding of the protein. Indeed, characterization of T356A, the phospho-ablative form, and T356D, the phospho-mimetic form of Orc1-2, revealed that only the phospho-ablative form retained the specific DNA binding. Genetic characterization and RNA-seq analyses further revealed that their corresponding mutants also exhibited expected phenotypes: orc1-2T356D no longer exhibited DNA damage responses upon NQO treatment, while the phospho-ablative mutant orc1-2T356A is not only more tolerant to DNA damage agents but also prolongs the window of the DNA damage response. Taken together, these results indicated that T356 phosphorylation deactivates Orc1-2, thereby attenuating the archaeal DNA damage response.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"54 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Absolute copy number aware CNV calling of sub-megabase segments in ultra-low coverage single-cell DNA sequencing data 超低覆盖单细胞DNA测序数据中亚兆基片段的绝对拷贝数感知CNV调用

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-09-20 DOI: 10.1093/nar/gkaf919

Solrun Kolbeinsdottir, Vasilios Zachariadis, Christian Sommerauer, Olli Lohi, Merja Heinäniemi, Martin Enge

{"title":"Absolute copy number aware CNV calling of sub-megabase segments in ultra-low coverage single-cell DNA sequencing data","authors":"Solrun Kolbeinsdottir, Vasilios Zachariadis, Christian Sommerauer, Olli Lohi, Merja Heinäniemi, Martin Enge","doi":"10.1093/nar/gkaf919","DOIUrl":"https://doi.org/10.1093/nar/gkaf919","url":null,"abstract":"Recent advances in ultra-low coverage whole-genome sequencing (WGS) of single cells have enabled detailed analysis of copy number variation at a throughput approaching that of single-cell RNA sequencing. However, downstream computational methods have not seen comparable advances and are largely adaptations of deep sequencing methodology with reduced precision. Here, we present ASCENT, a computational method built to take full advantage of modern direct tagmentation-based WGS at ultra-low depth. Using joint segmentation with high-resolution bins, we accurately detect small segments, achieving accurate copy number profiles even at 100 000 reads per cell. ASCENT implements true absolute copy state inference for single cells, based on statistical modeling of coverage rather than comparison to a reference, while taking variable segment copy state into account. Further, ASCENT implements per-segment copy-neutral loss of heterozygosity (LOH) calling without the need for non-tumor or bulk WGS reference. When applied to a pediatric B-ALL sample, ASCENT finds copy-neutral LOH in a small segment and a minor subclone defined by breakpoints missed in bulk WGS. Thus, by applying appropriate computational methods, single-cell WGS provides clear advantages over bulk, even at a relatively low cell number and sequencing depth.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"102 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Runaway evolution of telomeres in ascomycetous yeasts was accompanied by the replacement of ancestral telomeric proteins 子囊酵母端粒的失控进化伴随着祖先端粒蛋白的替换

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-09-20 DOI: 10.1093/nar/gkaf906

Filip Červenák, Sofia Virágová, Martina Sopkovičová, Dominik Kodada, Erik Galla, Regina Sepšiová, Katarína Procházková, Ľubomír Tomáška

{"title":"Runaway evolution of telomeres in ascomycetous yeasts was accompanied by the replacement of ancestral telomeric proteins","authors":"Filip Červenák, Sofia Virágová, Martina Sopkovičová, Dominik Kodada, Erik Galla, Regina Sepšiová, Katarína Procházková, Ľubomír Tomáška","doi":"10.1093/nar/gkaf906","DOIUrl":"https://doi.org/10.1093/nar/gkaf906","url":null,"abstract":"Telomeres are crucial parts of eukaryotic chromosomes, contributing to DNA replication, chromosome segregation, and genome stability. While in most phylogenetic lineages, telomere-maintenance systems are conserved, ascomycetous yeasts exhibit a high degree of variability in telomeric repeats and the associated proteins. The determinants that enabled this divergent evolutionary process, however, have been unclear. Here, we show that DNA-binding properties of yeast telomere-binding proteins (TBPs) support the scenario where the gradual divergence of telomeric repeats led to their replacement. We analyzed the DNA–protein interactions between Tay1p from Yarrowia lipolytica, Rap1p from Saccharomyces cerevisiae, and Taz1p from Schizosaccharomyces pombe and a set of telomeric repeats from several yeast species and delineated how the ancestral (Tay1p-like) TBPs were replaced by Rap1p (in budding yeasts) or Taz1p (in fission yeasts). We also postulate two different driving forces for these replacements: (i) Tay1p-to-Rap1p transition appears to be driven by differences in sequence preferences of Tay1p and Rap1p, while (ii) Taz1p became the principal TBP in fission yeast presumably due to its DNA-binding flexibility. Together, our results suggest that in telomeric DNA–protein complexes, the replacement of protein component triggered by the initial variation in DNA sequence space opens the door to further divergence in a runaway-style evolution.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"32 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Post-transcriptional control of KRAS: functional roles of 5′UTR RNA G-quadruplexes, long noncoding RNA, and hnRNPA1 KRAS转录后调控：5'UTR RNA g -四联体、长链非编码RNA和hnRNPA1的功能作用

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-09-20 DOI: 10.1093/nar/gkaf886

Ylenia Cortolezzis, Zahraa Othman, Francesca Agostini, Iman Ibrahim, Raffaella Picco, Gilmar F Salgado, Eros Di Giorgio, Luigi E Xodo

{"title":"Post-transcriptional control of KRAS: functional roles of 5′UTR RNA G-quadruplexes, long noncoding RNA, and hnRNPA1","authors":"Ylenia Cortolezzis, Zahraa Othman, Francesca Agostini, Iman Ibrahim, Raffaella Picco, Gilmar F Salgado, Eros Di Giorgio, Luigi E Xodo","doi":"10.1093/nar/gkaf886","DOIUrl":"https://doi.org/10.1093/nar/gkaf886","url":null,"abstract":"Previous studies have shown that human KRAS expression is regulated at the transcriptional level by G-quadruplex DNA structures within its promoter. Here we show an additional level of regulation involving a post-transcriptional mechanism centred on the 5′-untranslated region (5′UTR) of the messenger RNA (mRNA) characterized by G4 structures (rG4s). Long noncoding RNAs (lncRNAs) and the protein hnRNPA1 are also involved in this mechanism. RIP-seq confirmed the presence of rG4s in the 5′UTR. Deletion of the rG4 region using CRISPR/Cas9 resulted in a significant increase in KRAS mRNA levels, indicating the role of the 5′UTR in controlling mRNA levels. RIP shows that hnRNPA1 is recruited to the 5′UTR, where it unfolds the rG4 structures and potentially affects mRNA stability. In addition, lncRNAs transcribed from the LINC01750 locus can hybridize to the rG4 region of 5′UTR and form RNA duplexes leading to RNase III-assisted degradation of the targeted mRNA. Activation of the LINC01750 locus with dCas9-VP64 resulted in downregulation of KRAS mRNA, whereas its suppression with dCas9-KRAB led to upregulation of both KRAS mRNA and protein. Since lncRNA-mediated regulation of mRNA appears to be a crucial aspect of cellular homeostasis and its disruption contributes to various diseases, understanding these mechanisms may reveal promising new therapeutic targets.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"62 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Augmented kurtosis-based projection pursuit: a novel, advanced machine learning approach for multi-omics data analysis and integration 基于增强峰度的投影追踪：一种用于多组学数据分析和集成的新颖、先进的机器学习方法

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-09-20 DOI: 10.1093/nar/gkaf844

Fabian Bong, Ibrahim Ahmed, Nithya Ramakrishnan, Karla N Valenzuela-Valderas, Peter D Wentzell, Jasmine Barra, Tobias K Karakach

{"title":"Augmented kurtosis-based projection pursuit: a novel, advanced machine learning approach for multi-omics data analysis and integration","authors":"Fabian Bong, Ibrahim Ahmed, Nithya Ramakrishnan, Karla N Valenzuela-Valderas, Peter D Wentzell, Jasmine Barra, Tobias K Karakach","doi":"10.1093/nar/gkaf844","DOIUrl":"https://doi.org/10.1093/nar/gkaf844","url":null,"abstract":"Due to the heterogeneity of multi-omics data, exacting their maximum information potential remains a challenge. Whereas some solutions have been offered, most cannot overcome the large linear dynamic range associated with such data, while others require large biological effect sizes to produce meaningful models. Here, we (i) perform a comprehensive benchmarking of multi-omics data analysis tools, and (ii) introduce kurtosis-based projection pursuit analysis, augmented with classification and regression trees (kPPA-CART) as a robust, easy-to-implement alternative. Using ground truth data, we demonstrate that kPPA-CART exhibits superiority in inferring biological significance from low-intensity (low-count) features and studies with small biological effect sizes. Applying it to experimental breast cancer data from The Cancer Genome Atlas, we identify novel genes that cluster the samples into subtypes that mimic the canonical PAM50 classes with notable improvements. Validating with external metastatic breast cancer data from the AURORA US consortium, kPPA-CART identifies genes that are associated with poor event-free survival and additional clustering associated with increased tumor mutational burden. Finally, we provide an R package and an online implementation of kPPA-CART.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"3 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

APD6: the antimicrobial peptide database is expanded to promote research and development by deploying an unprecedented information pipeline. APD6：扩展抗菌肽数据库，通过部署前所未有的信息管道来促进研究和开发。

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-09-10 DOI: 10.1093/nar/gkaf860

Guangshun Wang,Cindy Schmidt,Xia Li,Zhe Wang

{"title":"APD6: the antimicrobial peptide database is expanded to promote research and development by deploying an unprecedented information pipeline.","authors":"Guangshun Wang,Cindy Schmidt,Xia Li,Zhe Wang","doi":"10.1093/nar/gkaf860","DOIUrl":"https://doi.org/10.1093/nar/gkaf860","url":null,"abstract":"The global antibiotic resistance issue constitutes a driving force for developing host defense antimicrobial peptides (AMPs) into a new generation of antibiotics. To facilitate this development, we report the antimicrobial peptide database version 6 (APD6) with (i) the consolidated database platform, (ii) the most comprehensive AMP information pipeline (AMPIP), and (iii) the expanded wheel of function. As of 18 March 2025, the APD6 platform housed records for 5188 peptides, including 3306 natural, 1380 synthetic, and 239 predicted AMPs with systematic classification schemes for each group. Based on the refined dataset, we present an updated view and findings on natural AMPs. Natural AMPs provide a fundamental dataset for peptide design and predicting potential AMPs. While current artificial intelligence prediction of AMPs is limited to activity and hemolysis, the APD6 provides new positive and negative datasets (e.g. pH, salt, serum effects, and resistance) for building advanced AI prediction models to identify more robust antibiotics. The AMPIP covers information ranging from peptide discovery, in vitro/in vivo activity and toxicity data, to clinical trials. In addition, the APD6 (available at https://aps.unmc.edu) contains an expanded wheel of peptide functions (e.g. anticancer and antidiabetic), allowing for developing peptide therapeutics outside the antibiotic arena.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"24 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

TCRdb 2.0: an updated T-cell receptor sequence database. TCRdb 2.0：更新的t细胞受体序列数据库。

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-09-09 DOI: 10.1093/nar/gkaf876

Tao Yue,Si-Yi Chen,Wen-Kang Shen,Yu Liao,Qian Lei,An-Yuan Guo

{"title":"TCRdb 2.0: an updated T-cell receptor sequence database.","authors":"Tao Yue,Si-Yi Chen,Wen-Kang Shen,Yu Liao,Qian Lei,An-Yuan Guo","doi":"10.1093/nar/gkaf876","DOIUrl":"https://doi.org/10.1093/nar/gkaf876","url":null,"abstract":"T-cell receptor (TCR) repertoire sequencing allows researchers to analyze millions of TCRs, providing unparalleled precision in understanding immune responses and enabling broad applications. However, existing TCR-related databases are based on a limited number of samples. Here, we present TCRdb2.0 (https://guolab.wchscu.cn/TCRdb2/#/), an updated and significantly expanded resource with enriched data and enhanced functionalities. TCRdb2.0 incorporates ∼700 million TCR sequences derived from 19 701 TCR-Seq samples across 46 tissues and 147 clinical conditions, making it the most comprehensive TCR sequence database to date. The homepage of TCRdb2.0 has powerful browsing, searching and downloading functions. It displays multiple features of TCR in sample and project levels. Compared to the previous release, TCRdb2.0 has the following major improvements: (i) a substantial increase of TCR sequences, from 277 million to ∼700 million; (ii) inclusion of TCR sequences from Gamma delta (γδ) T cells; (iii) integration of therapy-related TCR-Seq datasets, such as programmed cell death 1 (PD-1) blockade immunotherapy; (iv) construction of the largest TCR sequence reference from healthy samples; and (v) redesign of a new search and download function, enabling flexible queries and downloads. With its extensive data and user-friendly web interface, TCRdb2.0 will serve as an invaluable resource for functional studies of TCRs in both health and disease.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"17 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CRISPR/Cas12a DTR system: a topology-guided Cas12a assay for specific dual detection of RNA and DNA targets. CRISPR/Cas12a DTR系统：一种拓扑引导的Cas12a检测，用于特异性双重检测RNA和DNA靶标。

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-09-05 DOI: 10.1093/nar/gkaf893

Qingyuan Jiang,Shuqi Jin,Zhichao Qin,Junqi Zhang,Ruyi He,Zhuo Chen,Bin Qiao,Jie Qiao,Yi Liu

{"title":"CRISPR/Cas12a DTR system: a topology-guided Cas12a assay for specific dual detection of RNA and DNA targets.","authors":"Qingyuan Jiang,Shuqi Jin,Zhichao Qin,Junqi Zhang,Ruyi He,Zhuo Chen,Bin Qiao,Jie Qiao,Yi Liu","doi":"10.1093/nar/gkaf893","DOIUrl":"https://doi.org/10.1093/nar/gkaf893","url":null,"abstract":"The CRISPR/Cas12a technology has revolutionized molecular diagnostics. However, existing Cas12a systems depend on continuous target DNA activation, which limits them to single-target detection. In this study, we developed a novel topology-guided Cas12a system, the double-target responsive (DTR) system, capable of being activated by noncontiguous dual RNA/DNA targets. The DTR system employs two split CRISPR RNA (crRNA) fragments and two Cas12a proteins that cooperatively reconstitute upon recognizing two nucleic acid activators. We demonstrated the DTR system's ability to specifically detect dual nucleic acid substrates in a single readout, achieving a detection limit of 78 fM for RNA and exceptional specificity for single-nucleotide variations. Additionally, we successfully applied the DTR system to clinical samples, enabling simultaneous detection of two oral squamous cell carcinoma-related microRNAs (miR-155 and miR-let-7a), thereby distinguishing healthy individuals from patients. This work establishes an efficient Cas12a-based platform for sensitive, simultaneous, and discriminative detection of RNA and DNA targets, enhancing the versatility of Cas12a in analytical detection and clinical diagnosis.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"38 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Crystal structures of distinct parallel and antiparallel DNA G-quadruplexes reveal structural polymorphism in C9orf72 G4C2 repeats. 不同的平行和反平行DNA g -四联体的晶体结构揭示了C9orf72 G4C2重复序列的结构多态性。

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-09-05 DOI: 10.1093/nar/gkaf879

Yanyan Geng,Changdong Liu,Haitao Miao,Monica Ching Suen,Yuanyuan Xie,Bingchang Zhang,Wanhong Han,Caiming Wu,Haixia Ren,Xueqin Chen,Hwan-Ching Tai,Zhanxiang Wang,Guang Zhu,Qixu Cai

{"title":"Crystal structures of distinct parallel and antiparallel DNA G-quadruplexes reveal structural polymorphism in C9orf72 G4C2 repeats.","authors":"Yanyan Geng,Changdong Liu,Haitao Miao,Monica Ching Suen,Yuanyuan Xie,Bingchang Zhang,Wanhong Han,Caiming Wu,Haixia Ren,Xueqin Chen,Hwan-Ching Tai,Zhanxiang Wang,Guang Zhu,Qixu Cai","doi":"10.1093/nar/gkaf879","DOIUrl":"https://doi.org/10.1093/nar/gkaf879","url":null,"abstract":"The abnormal expansion of GGGGCC (G4C2) repeats in the noncoding region of the C9orf72 gene is a major genetic cause of two devastating neurodegenerative disorders, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These G4C2 repeats are known to form G-quadruplex (G4) structures, which are hypothesized to contribute to disease pathogenesis. Here, we demonstrated that four DNA G4C2 repeats can fold into two structurally distinct G4 conformations: a parallel and an antiparallel topology. The high-resolution crystal structure of the parallel G4 reveals an eight-layered dimeric assembly, formed by two identical monomeric units. Each unit contains four stacked G-tetrads connected by three propeller CC loops and is stabilized through 5'-to-5' π-π interactions and coordination with a central K+ ion. Notably, the 3'-ending cytosines form a C·C+·C·C+ quadruple base pair stacking onto the adjacent G-tetrad layer. In contrast, the antiparallel G4 adopts a four-layered monomeric structure with three edgewise loops, where the C6 and C18 bases engage in stacking interaction with neighboring G-tetrad via a K+ ion. These structurally distinct G-quadruplexes provide mechanistic insights into C9orf72-associated neurodegeneration and offer potential targets for the development of structure-based therapeutic strategies for ALS and FTD.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"100 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145031949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0