Nucleic Acids Research最新文献

Linkage-based ortholog refinement in bacterial pangenomes with CLARC. 利用CLARC对细菌泛基因组进行基于连锁的同源精化。

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-06-20 DOI: 10.1093/nar/gkaf488

Indra González Ojeda, Samantha G Palace, Pamela P Martinez, Taj Azarian, Lindsay R Grant, Laura L Hammitt, William P Hanage, Marc Lipsitch

{"title":"Linkage-based ortholog refinement in bacterial pangenomes with CLARC.","authors":"Indra González Ojeda, Samantha G Palace, Pamela P Martinez, Taj Azarian, Lindsay R Grant, Laura L Hammitt, William P Hanage, Marc Lipsitch","doi":"10.1093/nar/gkaf488","DOIUrl":"https://doi.org/10.1093/nar/gkaf488","url":null,"abstract":"<p><p>Bacterial genomes exhibit significant variation in gene content and sequence identity. Pangenome analyses explore this diversity by classifying genes into core and accessory clusters of orthologous groups (COGs). However, strict sequence identity cutoffs can misclassify divergent alleles as different genes, inflating accessory gene counts. CLARC (Connected Linkage and Alignment Redefinition of COGs) (https://github.com/IndraGonz/CLARC) improves pangenome analyses by condensing accessory COGs using functional annotation and linkage information. Through this approach, orthologous groups are consolidated into more practical units of selection. Analyzing 8000+ Streptococcus pneumoniae genomes, CLARC reduced accessory gene estimates by >30% and improved evolutionary predictions based on accessory gene frequencies. CLARC is effective across different bacterial species, making it a broadly applicable tool for comparative genomics. By refining COG definitions, CLARC offers critical insights into bacterial evolution, aiding genetic studies across diverse populations.</p>","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 12","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144333576","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

Catalytic-state structure of Candidatus Hydrogenedentes Cas12b revealed by cryo-EM studies. cro - em研究Candidatus hydrogenentes Cas12b的催化态结构。

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-06-20 DOI: 10.1093/nar/gkaf519

Ye Li,Jian Li,Xiaotong Pei,Jingjing Wei,Jianhua Gan,Jinzhong Lin

{"title":"Catalytic-state structure of Candidatus Hydrogenedentes Cas12b revealed by cryo-EM studies.","authors":"Ye Li,Jian Li,Xiaotong Pei,Jingjing Wei,Jianhua Gan,Jinzhong Lin","doi":"10.1093/nar/gkaf519","DOIUrl":"https://doi.org/10.1093/nar/gkaf519","url":null,"abstract":"The CRISPR-Cas (clustered regularly interspaced short palindromic repeats and CRISPR-associated protein) systems are adaptive immune mechanisms that play critical roles in defending archaea and bacteria against invading entities. These systems can be divided into two classes, with class 2 comprising three types (II, V, and VI). Because of their ability to cleave double-stranded DNA, many class 2 CRISPR-Cas proteins have been harnessed as genome editing tools. Unlike the well-studied type II Cas9 proteins, the structural studies of the type V-B Cas12b proteins are limited, hindering their engineering and broader application. Here, we report four complex structures of ChCas12b, which reveal many unique structural features. The folding of the single guide RNA (sgRNA) of ChCas12b is distinct from that of AacCas12b and BthCas12b. Notably, many of these unique features are involved in ChCas12b-sgRNA interaction, suggesting that they are co-evolved. While ChCas12b shares a conserved two-cation-assisted catalytic mechanism with its homologs, it recognizes a longer guide:target heteroduplex, potentially offering higher fidelity in DNA editing. Altogether, our studies suggested that Cas12b family proteins exhibit significant diversity in their folding, sgRNA and target DNA binding. In the future, it is worth characterizing more representative proteins to identify CRISPR-Cas proteins with higher gene editing ability and fidelity.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"16 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144329043","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

Switchable RNA motifs for dynamic transcriptional control of RNA condensates. 可切换RNA基序用于RNA凝聚物的动态转录控制。

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-06-20 DOI: 10.1093/nar/gkaf497

Anli A Tang,Martin Vincent Gobry,Shiyi Li,Ebbe Sloth Andersen,Elisa Franco

{"title":"Switchable RNA motifs for dynamic transcriptional control of RNA condensates.","authors":"Anli A Tang,Martin Vincent Gobry,Shiyi Li,Ebbe Sloth Andersen,Elisa Franco","doi":"10.1093/nar/gkaf497","DOIUrl":"https://doi.org/10.1093/nar/gkaf497","url":null,"abstract":"RNA-driven phase separation is emerging as a promising approach for engineering biomolecular condensates with diverse functionalities. Condensates form thanks to weak yet specific RNA-RNA interactions established by design via complementary sequence domains. Here, we demonstrate how RNA condensates formed by star-shaped RNA motifs, or nanostars, can be dynamically controlled when the motifs include additional linear or branch-loop domains that facilitate access of regulatory RNA molecules to the nanostar interaction domains. We show that condensates dissolve in the presence of RNA \"invaders\" that occlude selected nanostar bonds and reduce the valency of the nanostars, preventing phase separation. We further demonstrate that the introduction of \"anti-invader\" strands, complementary to the invaders, makes it possible to restore condensate formation. An important aspect of our experiments is that we demonstrate these behaviors in one-pot reactions, where RNA nanostars, invaders, and anti-invaders are simultaneously transcribed in vitro using short DNA templates. Our results lay the groundwork for engineering RNA-based assemblies with tunable, reversible condensation, providing a promising toolkit for synthetic biology applications requiring responsive, self-organizing biomolecular materials.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"14 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144329042","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

An engineered glutamic acid tRNA for efficient suppression of pathogenic nonsense mutations. 一种工程谷氨酸tRNA有效抑制致病性无义突变。

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-06-20 DOI: 10.1093/nar/gkaf532

Caitlin Specht,Alejandro Tapia,Sarah Penrod,Gabriela A Soriano,Aya Awawdeh,Sarah A Alshawi,Cody A White,Jean-Denis Beaudoin,Emma H Doud,Oscar Vargas-Rodriguez,Yunjie Huang,Jeffery M Tharp

{"title":"An engineered glutamic acid tRNA for efficient suppression of pathogenic nonsense mutations.","authors":"Caitlin Specht,Alejandro Tapia,Sarah Penrod,Gabriela A Soriano,Aya Awawdeh,Sarah A Alshawi,Cody A White,Jean-Denis Beaudoin,Emma H Doud,Oscar Vargas-Rodriguez,Yunjie Huang,Jeffery M Tharp","doi":"10.1093/nar/gkaf532","DOIUrl":"https://doi.org/10.1093/nar/gkaf532","url":null,"abstract":"Nonsense mutations that introduce premature termination codons (PTCs) into protein-coding genes are responsible for numerous genetic diseases; however, there are currently no effective treatment options for individuals affected by these mutations. One approach to combat nonsense-related diseases relies on the use of engineered suppressor transfer RNAs (sup-tRNAs) that facilitate translational stop codon readthrough, thereby restoring full-length protein synthesis. While several sup-tRNAs have shown promising results in preclinical models, many exhibit low PTC suppression efficiency, precluding their use as therapeutics. For example, glutamic acid (Glu) codons represent one of the most common sites for nonsense mutations, yet existing sup-tRNAs are ineffective at suppressing Glu-to-Stop mutations. To address this limitation, here we describe a rationally designed sup-tRNA (tRNAGluV13) with greatly improved ability to suppress PTCs occurring at Glu codons. We demonstrate that tRNAGluV13 efficiently restores protein synthesis from multiple nonsense-containing reporter genes, faithfully installing Glu in response to PTCs. Additionally, we demonstrate that tRNAGluV13 can functionally rescue pathogenic PTCs that cause hereditary breast and ovarian cancer syndrome and cystic fibrosis. The ability of tRNAGluV13 to effectively suppress one of the most common PTC mutations should greatly expand the potential of sup-tRNA-based therapeutics.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"24 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144329044","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

A rational engineering strategy for structural dynamics modulation enables target specificity enhancement of the Cas9 nuclease. 合理的结构动力学调节工程策略可以增强Cas9核酸酶的靶特异性。

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-06-20 DOI: 10.1093/nar/gkaf535

Keewon Sung,Youngri Jung,Nahye Kim,Yong-Woo Kim,Hyongbum Henry Kim,Seong Keun Kim,Sangsu Bae

{"title":"A rational engineering strategy for structural dynamics modulation enables target specificity enhancement of the Cas9 nuclease.","authors":"Keewon Sung,Youngri Jung,Nahye Kim,Yong-Woo Kim,Hyongbum Henry Kim,Seong Keun Kim,Sangsu Bae","doi":"10.1093/nar/gkaf535","DOIUrl":"https://doi.org/10.1093/nar/gkaf535","url":null,"abstract":"Structural dynamics of an enzyme plays a crucial role in enzymatic activity and substrate specificity, yet rational engineering of the dynamics for improved enzymatic properties remains a challenge. Here, we present a new biochemical strategy of intermediate state stabilization that modulates the multistep dynamic mechanisms of enzyme reactions to improve substrate specificity. We employ this strategy to enhance CRISPR-Cas9 nuclease specificity. By incorporating positively charged residues into the noncatalytic REC2 domain of Cas9, we stabilize the REC2-DNA interaction that forms exclusively in a catalytically inactive intermediate conformation of the Cas9 complex. This enables off-target trapping in the inactive conformation and thus reduces off-target cleavage in human cells. Furthermore, we combine the REC2 modification with mutations in previous rational variants, leading to the development of a combinational variant named Correct-Cas9, which connotes \"combined with rationally engineered REC-Two\" Cas9. Assessed by high-throughput analysis at thousands of target sequences, Correct-Cas9 exhibits increased target specificity compared to its parental variants, demonstrating a synergy between our strategy and previous rational approaches. Our method of intermediate state stabilization, either alone or combined with conventional approaches, could be applied to various nucleic acid-processing enzymes that undergo conformational changes upon target binding, to enhance their target specificity effectively.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"236 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144329045","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

An endogenous retroviral element co-opts an upstream regulatory sequence to achieve somatic expression and mobility 内源性逆转录病毒元件协同上游调控序列实现体细胞表达和迁移

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-06-16 DOI: 10.1093/nar/gkaf485

Natalia Rubanova, Darshika Singh, Louis Barolle, Fabienne Chalvet, Sophie Netter, Mickaël Poidevin, Nicolas Servant, Allison J Bardin, Katarzyna Siudeja

{"title":"An endogenous retroviral element co-opts an upstream regulatory sequence to achieve somatic expression and mobility","authors":"Natalia Rubanova, Darshika Singh, Louis Barolle, Fabienne Chalvet, Sophie Netter, Mickaël Poidevin, Nicolas Servant, Allison J Bardin, Katarzyna Siudeja","doi":"10.1093/nar/gkaf485","DOIUrl":"https://doi.org/10.1093/nar/gkaf485","url":null,"abstract":"Retrotransposons, multi-copy sequences that propagate via copy-and-paste mechanisms, occupy large portions of eukaryotic genomes. A great majority of their manifold copies remain silenced in somatic cells; nevertheless, some are transcribed, often in a tissue-specific manner, and a small fraction retains its ability to mobilize. While it is well characterized that retrotransposon sequences may provide cis-regulatory elements for neighboring genes, how their own expression and mobility are achieved is not well understood. Here, using long-read DNA sequencing, we characterize somatic retrotransposition in the Drosophila intestine. We show that retroelement mobility does not change significantly upon aging and is limited to very few active sub-families. Importantly, we identify a donor locus of an endogenous LTR (long terminal repeat) retroviral element rover, active in the intestinal tissue. We reveal that gut activity of the rover donor copy depends on its genomic environment. Without affecting local gene expression, the copy co-opts its upstream genomic sequence, rich in transcription factor binding sites, for somatic expression. Further, we show that escargot, a snail-type transcription factor, can drive transcriptional activity of the active rover copy. These data provide new insights into how locus-specific features allow active retrotransposons to produce functional transcripts and mobilize in a somatic lineage.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"179 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144296054","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

Nat10 maintains the homeostasis of pluripotent and 2-cell-like states in mouse embryonic stem cells through mRNA cytidine acetylation Nat10通过mRNA胞苷乙酰化维持小鼠胚胎干细胞多能和2细胞样状态的稳态

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-06-16 DOI: 10.1093/nar/gkaf504

Guofeng Feng, Guoxing Yin, Yusheng Liu, Chang Liu, Jie Li, Jiangtao Lu, Yongqin Yu, Ziyi Jin, Yiwei Wu, Yanbin Yue, Xiufang Gao, Jiaqiang Wang, Falong Lu, Lin Liu

{"title":"Nat10 maintains the homeostasis of pluripotent and 2-cell-like states in mouse embryonic stem cells through mRNA cytidine acetylation","authors":"Guofeng Feng, Guoxing Yin, Yusheng Liu, Chang Liu, Jie Li, Jiangtao Lu, Yongqin Yu, Ziyi Jin, Yiwei Wu, Yanbin Yue, Xiufang Gao, Jiaqiang Wang, Falong Lu, Lin Liu","doi":"10.1093/nar/gkaf504","DOIUrl":"https://doi.org/10.1093/nar/gkaf504","url":null,"abstract":"Naïve mouse embryonic stem cells (mESCs) are characterized by a mixed population of cells in an interconvertible pluripotent state and a totipotent 2-cell (2C)-like state. It remains to be understood how the pluripotent state is maintained while the 2C-like state is suppressed. We show that N-acetyltransferase 10 (Nat10) maintains the pluripotent state and suppresses the 2C-like state in mESCs through mRNA modification and stabilization. Nat10 as a nucleolar protein may indirectly interact with heterochromatin through Ncl. Nat10 catalyzes the N4-acetylcytidine (ac4C) modification of mRNAs encoding the key pluripotency genes including Oct4,Esrrb and Zfp42 and enhances their mRNA stability, thus increasing their protein levels for pluripotency. Moreover, Nat10 acetylates and stabilizes heterochromatin modifiers such as Kap1 mRNA and protein to repress the 2C genes by maintaining the H3K9me3 complex. Together, these findings highlight critical roles for Nat10 in maintaining the pluripotency network and repressing the 2C-like program via mRNA ac4C modification, providing insights into the transition between pluripotent and totipotent states in mESCs.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"230 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144296056","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

Methylation of mycovirus DNA is mediated by the RNAi machinery in vegetative hyphae of Fusarium graminearum 在小麦镰刀菌营养菌丝中，RNAi机制介导了分枝病毒DNA的甲基化

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-06-16 DOI: 10.1093/nar/gkaf478

Yanfei Wang, Wei Chen, Lihang Zhang, Shuangchao Wang, Jin-Rong Xu, Lihua Guo

{"title":"Methylation of mycovirus DNA is mediated by the RNAi machinery in vegetative hyphae of Fusarium graminearum","authors":"Yanfei Wang, Wei Chen, Lihang Zhang, Shuangchao Wang, Jin-Rong Xu, Lihua Guo","doi":"10.1093/nar/gkaf478","DOIUrl":"https://doi.org/10.1093/nar/gkaf478","url":null,"abstract":"DNA cytosine methylation is an important epigenetic mechanism for transposon silencing and gene regulation in fungi, particularly during sexual reproduction. However, its occurrence in vegetative hyphae and role in defense against mycoviruses is unclear. In this study, we demonstrated that genomic-wide cytosine methylation of the tripartite genomovirus FgGMTV1 occurs in the hyphae of Fusarium graminearum, a destructive pathogen of wheat and barley worldwide. Elevated methylation levels were predominantly observed in the promoter regions of FgGMTV1, with the highest level reaching 55.87% in the DNA-C fragment MeC5. Methylation of the Rep promoter in DNA-A was showed to be mediated by DNA methyltransferase DIM2 and lead to its transcriptional activity suppression, resulting in a significant reduction in virus accumulation. Furthermore, we uncovered that small RNAs (sRNAs) derived from FgGMTV1 direct the methylation of viral DNA and integrated foreign promoters, which requires the core components of the RNAi machinery, including the Ago and Dicer genes. Deletion of dcl1/2 or ago1/2 in FgGMTV1-infected strains resulted in an increase in virus accumulation and defects in hyphal growth, stress response, and plant infection. Taken together, our findings reveal that RNAi-mediated DNA methylation occurs in vegetative hyphae and plays a crucial role in antiviral defense mechanisms in fungi.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"90 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144296058","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

Super-enhancer-mediated circRNAs exhibit high splicing circularization diversity and transcriptional activity 超增强子介导的环状rna表现出高剪接环化多样性和转录活性

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-06-13 DOI: 10.1093/nar/gkaf505

Shaodong Huang, Yulong Han, Yiran Liu, Lina Bu, Chenyang Wu, Ziyan Rao, Chuan Ye, Hansen Cheng, Yunxi Liao, Yunan Sun, Yushu Zou, Zixu Wang, Bryan-Yu Sun, Shu Meng, Dongyu Zhao

{"title":"Super-enhancer-mediated circRNAs exhibit high splicing circularization diversity and transcriptional activity","authors":"Shaodong Huang, Yulong Han, Yiran Liu, Lina Bu, Chenyang Wu, Ziyan Rao, Chuan Ye, Hansen Cheng, Yunxi Liao, Yunan Sun, Yushu Zou, Zixu Wang, Bryan-Yu Sun, Shu Meng, Dongyu Zhao","doi":"10.1093/nar/gkaf505","DOIUrl":"https://doi.org/10.1093/nar/gkaf505","url":null,"abstract":"Circular RNAs (circRNAs), an emerging subclass of noncoding RNAs, have been increasingly recognized as critical regulators in diverse biological functions and cellular processes. Despite their functional significance, the epigenetic mechanisms governing circRNA biogenesis remain poorly understood. Our study reveals that H3K27ac-marked super-enhancers (SEs) significantly enhance both circRNA splicing circularization diversity and transcriptional activation of their host genes. Intriguingly, other histone modifications—including H3K4me3, H3K36me3, H3K27me3, and H3K9me3—exhibit distinct regulatory effects on circRNA transcriptional activity. Through comprehensive analysis of 195 transcriptomic profiles, we identified a pan-cancer epigenomic tumor-suppressor signature termed CircRNA Isoform Reduction for Shortened Enhancers in cancer (CIRSE). Notably, CIRSE demonstrates strong prognostic potential in lung adenocarcinoma, as validated by comprehensive survival analyses. Combining Nanopore sequencing with CLIP-Seq approaches, we further elucidated the dual regulatory mechanism involving circRNA stability maintenance and back-splicing junction selection mediated by specific RNA-binding proteins. Functional validation confirmed that CIRSE-defined tumor-suppressive circRNAs are essential for maintaining malignant phenotypes in cancer models. Our findings not only provide mechanistic insights into the epigenetic regulation of circRNAs, but also pave the way for mutation-agnostic discovery of tumor-suppressive circRNAs in precision oncology applications.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"9 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288203","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

Efficient coordination between the winged helix domain and the aromatic-rich loop restructures the ATPase domain and facilitates DNA unwinding by human RECQ1 翼状螺旋结构域和富芳香环之间的有效协调重组了atp酶结构域，并促进了人类RECQ1对DNA的解绕

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-06-13 DOI: 10.1093/nar/gkaf489

Tulika Das, Swagata Mukhopadhyay, Amit K Das, Agneyo Ganguly

{"title":"Efficient coordination between the winged helix domain and the aromatic-rich loop restructures the ATPase domain and facilitates DNA unwinding by human RECQ1","authors":"Tulika Das, Swagata Mukhopadhyay, Amit K Das, Agneyo Ganguly","doi":"10.1093/nar/gkaf489","DOIUrl":"https://doi.org/10.1093/nar/gkaf489","url":null,"abstract":"RecQ helicases can unwind a wide spectrum of DNA structures and thereby protect the cells from genome instability. Unwinding mechanisms have been extensively studied for bacterial and human RecQ helicases. DNA-induced winged helix (WH) domain repositioning and allosteric remodeling of the ATPase domain have been shown to be important for unwinding activity of bacterial RecQ helicases. In contrast, no such altered conformational state was observed for human RECQ1 upon DNA or nucleotide binding. In this study, we have crystallized and characterized an engineered RECQ1 containing a flexible glycine serine-rich linker inserted between the zinc binding and WH domains. The linker containing construct exhibits more efficient DNA binding and unwinding activity. A crystal structure of the engineered RECQ1 in complex with DNA exhibits conformational rearrangements of the helicase and WH domains, resulting in a more compact structure. Our structure, for the first time, demonstrates that alteration of the distance between the tip of the β-hairpin and the ARL favors DNA binding and remodels the ATPase domain, leading to alteration in substrate recognition and unwinding activity. These structural rearrangements are necessary for efficient coordination between the WH domain and the helicase domain, coupling DNA binding and ATP hydrolysis to strand separation.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"13 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144288204","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