Nucleic Acids Research最新文献_第6页

GPATCH4 functions as a regulator of nucleolar R-loops in hepatocellular carcinoma cells. GPATCH4在肝癌细胞中作为核仁r环的调节因子。

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-05-22 DOI: 10.1093/nar/gkaf438

Yi-Ming Zhao,Yan Jiang,Jin-Zhu Wang,Shang Cao,Hong Zhu,Wei-Kang Wang,Jian Yu,Jiaquan Liu,Jingyi Hui

{"title":"GPATCH4 functions as a regulator of nucleolar R-loops in hepatocellular carcinoma cells.","authors":"Yi-Ming Zhao,Yan Jiang,Jin-Zhu Wang,Shang Cao,Hong Zhu,Wei-Kang Wang,Jian Yu,Jiaquan Liu,Jingyi Hui","doi":"10.1093/nar/gkaf438","DOIUrl":"https://doi.org/10.1093/nar/gkaf438","url":null,"abstract":"Emerging evidence suggests that dysregulated RNA-binding proteins (RBPs) are associated with a wide variety of cancers. However, the exact roles and pathways of RBPs in the tumorigenesis of hepatocellular carcinoma (HCC), the most common subtype of liver cancer, remain largely unknown. Here, we systematically searched for altered RBP candidates in HCC through multi-omics data integrative analyses and identified that GPATCH4 gene is amplified in >70% HCC patients and its high expression predicts poor prognosis. We mapped the in vivo RNA binding sites of GPATCH4 by iCLIP-seq and characterized that GPATCH4 primarily bound ribosomal RNA (rRNAs). GPATCH4 promoted HCC cell proliferation and transformation both in vitro and in vivo through increasing rRNA transcription and global protein synthesis. GPATCH4 is mainly localized in the nucleolus and helps to unwind RNA loops formed at the rDNA through interacting with DDX21 via its C-terminal intrinsically disordered region. Removal of accumulated R-loops induced by GPATCH4 depletion rescued decreased rRNA transcription and cell proliferation. Taken together, we characterized the understudied GPATCH4 as an RBP with oncogenic function in HCC and revealed a new mechanism by which GPATCH4 functions as a regulator of nucleolar R-loops to control rRNA transcription through interacting with DDX21.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"9 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114274","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

Ribosomal expansion segment contributes to translation fidelity via N-terminal processing of ribosomal proteins. 核糖体扩展段通过核糖体蛋白的n端加工来保证翻译的保真度。

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-05-22 DOI: 10.1093/nar/gkaf448

Riku Nagai, Olivia L Milam, Tatsuya Niwa, William J Howell, Jacob A Best, Hideji Yoshida, Carver D Freeburg, John M Koomen, Kotaro Fujii

{"title":"Ribosomal expansion segment contributes to translation fidelity via N-terminal processing of ribosomal proteins.","authors":"Riku Nagai, Olivia L Milam, Tatsuya Niwa, William J Howell, Jacob A Best, Hideji Yoshida, Carver D Freeburg, John M Koomen, Kotaro Fujii","doi":"10.1093/nar/gkaf448","DOIUrl":"10.1093/nar/gkaf448","url":null,"abstract":"Eukaryotic ribosomes exhibit higher mRNA translation fidelity than prokaryotic ribosomes, partly due to eukaryote-specific ribosomal RNA (rRNA) insertions. Among these, expansion segment 27L (ES27L) on the 60S subunit enhances fidelity by anchoring methionine aminopeptidase (MetAP) at the nascent protein exit tunnel, accelerating co-translational N-terminal initiator methionine (iMet) processing. However, the mechanisms by which iMet processing influences translation fidelity remain unknown. Using yeast in vitro translation (IVT) systems, we found that inhibiting co-translational iMet processing does not impact ribosome decoding of ongoing peptide synthesis. Instead, our novel method to monitor iMet processing in vivo revealed that ribosomes purified from strains lacking MetAP ribosomal association (ES27L Δb1-4) or major yeast MetAP (Δmap1) increase iMet retention on ribosomal proteins (RPs). Given the densely packed structure of ribosomes, iMet retention on RPs may distort ribosomal structure and impair its function. Indeed, reconstituted IVT systems containing iMet-retaining ribosome subunits from ES27L Δb1-4 strain, combined with translation factors from wild-type strains, elucidated that iMet retention on the 40S ribosomal subunit causes translation errors. Our study demonstrated the critical role of ES27L in adjusting ribosome association of universally conserved MetAP enzyme to fine-tune iMet processing of key RPs, thereby ensuring the structural integrity and functional accuracy of eukaryotic ribosomes.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 10","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12117404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144160623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CorrAdjust unveils biologically relevant transcriptomic correlations by efficiently eliminating hidden confounders. CorrAdjust通过有效地消除隐藏的混杂因素揭示生物学相关的转录组相关性。

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-05-22 DOI: 10.1093/nar/gkaf444

Stepan Nersisyan, Phillipe Loher, Isidore Rigoutsos

{"title":"CorrAdjust unveils biologically relevant transcriptomic correlations by efficiently eliminating hidden confounders.","authors":"Stepan Nersisyan, Phillipe Loher, Isidore Rigoutsos","doi":"10.1093/nar/gkaf444","DOIUrl":"10.1093/nar/gkaf444","url":null,"abstract":"Correcting for confounding variables is often overlooked when computing RNA-RNA correlations, even though it can profoundly affect results. We introduce CorrAdjust, a method for identifying and correcting such hidden confounders. CorrAdjust selects a subset of principal components to residualize from expression data by maximizing the enrichment of \"reference pairs\" among highly correlated RNA-RNA pairs. Unlike traditional machine learning metrics, this novel enrichment-based metric is specifically designed to evaluate correlation data and provides valuable RNA-level interpretability. CorrAdjust outperforms current state-of-the-art methods when evaluated on 25 063 human RNA-seq datasets from The Cancer Genome Atlas, the Genotype-Tissue Expression project, and the Geuvadis collection. In particular, CorrAdjust excels at integrating small RNA and mRNA sequencing data, significantly enhancing the enrichment of experimentally validated miRNA targets among negatively correlated miRNA-mRNA pairs. CorrAdjust, with accompanying documentation and tutorials, is available at https://tju-cmc-org.github.io/CorrAdjust.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 10","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A role for pH dynamics regulating transcription factor DNA-binding selectivity. pH动态调节转录因子dna结合选择性的作用。

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-05-22 DOI: 10.1093/nar/gkaf474

Kyle P Kisor, Diego Garrido Ruiz, Matthew P Jacobson, Diane L Barber

{"title":"A role for pH dynamics regulating transcription factor DNA-binding selectivity.","authors":"Kyle P Kisor, Diego Garrido Ruiz, Matthew P Jacobson, Diane L Barber","doi":"10.1093/nar/gkaf474","DOIUrl":"10.1093/nar/gkaf474","url":null,"abstract":"Intracellular pH (pHi) dynamics regulates diverse cell processes such as proliferation, dysplasia, and differentiation, often mediated by the protonation state of a functionally critical histidine residue in endogenous pH sensing proteins. How pHi dynamics can directly regulate gene expression or whether transcription factors can function as pH sensors has received limited attention. We tested the prediction that transcription factors with a histidine in their DNA-binding domain (DBD) that forms hydrogen bonds with nucleotides can have pH-regulated activity, which is relevant to more than 85 transcription factors in distinct families, including FOX, KLF, SOX, and MITF/Myc. Focusing on FOX family transcription factors, we use unbiased SELEX-seq to identify pH-dependent DNA-binding motif preferences and confirm pH-regulated binding affinities for FOXC2, FOXM1, and FOXN1 to a canonical FkhP DNA motif that are greater at pH 7.0 compared with pH 7.5 and for FOXN1 to a preferred FHL motif at higher pHi in cells. For FOXC2, we also find that greater activity for an FkhP motif at lower pH is dependent on a conserved histidine (His122) in the DBD. ChIP-seq and RNA-seq with FOXC2 also reveal pH-dependent differences in enriched promoter motifs. Our findings identify pH-regulated transcription factor-DNA binding selectivity with relevance to how pHi dynamics can regulate gene expression for myriad cell behaviours.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 10","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SARS-CoV-2 point mutations are over-represented in terminal loops of RNA stem-loop structures that can be resolved by Nsp13 helicase in a unique manner with respect to nucleotide dependence. SARS-CoV-2点突变在RNA茎环结构的末端环中有过多的表现，这些突变可以通过Nsp13解旋酶以核苷酸依赖的独特方式解决。

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-05-22 DOI: 10.1093/nar/gkaf447

Adaira J Dumm,Andrew Y Zheng,Thomas J Butler,Tomasz Kulikowicz,Joe C George,Pierce T Bombard,Joshua A Sommers,Jun Ding,Robert M Brosh

{"title":"SARS-CoV-2 point mutations are over-represented in terminal loops of RNA stem-loop structures that can be resolved by Nsp13 helicase in a unique manner with respect to nucleotide dependence.","authors":"Adaira J Dumm,Andrew Y Zheng,Thomas J Butler,Tomasz Kulikowicz,Joe C George,Pierce T Bombard,Joshua A Sommers,Jun Ding,Robert M Brosh","doi":"10.1093/nar/gkaf447","DOIUrl":"https://doi.org/10.1093/nar/gkaf447","url":null,"abstract":"To improve health outcomes for COVID-19 (coronavirus disease 2019) patients, the factors that influence coronavirus genome variation need to be ascertained. The SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) genome is rich in predicted RNA secondary structures, particularly stem-loops (SLs) formed by intramolecular base pairing within palindromic sequences. We analyzed the NCBI Virus collection of SARS-CoV-2 genome sequences from COVID-19 individuals to map variants relative to SL structural elements. Point mutations in the SARS-CoV-2 genome, with a C-to-U transition bias, were over-represented in unpaired nucleotides and, more specifically, within the terminal loops of RNA SL structures. As the sole helicase encoded by SARS-CoV-2, Nsp13 may operate in the timely resolution of secondary RNA structures to facilitate SARS-CoV-2 RNA copying or processing. We characterized Nsp13 to resolve SARS-CoV-2 sequence-derived unimolecular RNA SL substrates and determined that it does so in a functionally cooperative manner. In addition to ATP, Nsp13 resolves the unimolecular RNA SL structure in the absence of nucleotide, in contrast to the strict ATP requirement for a bimolecular RNA forked duplex. We suggest a model in which a series of binary and ternary complex interactions of Nsp13 with nucleotide and/or RNA SL pose mechanistic implications for RNA SL resolution.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"96 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144146190","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

Comprehensive mutational analysis of the sequence-function relationship within a viral internal ribosome entry site. 病毒内核糖体进入位点序列-功能关系的综合突变分析。

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-05-22 DOI: 10.1093/nar/gkaf445

Sabrina G Grunseich,Scott A Strobel

{"title":"Comprehensive mutational analysis of the sequence-function relationship within a viral internal ribosome entry site.","authors":"Sabrina G Grunseich,Scott A Strobel","doi":"10.1093/nar/gkaf445","DOIUrl":"https://doi.org/10.1093/nar/gkaf445","url":null,"abstract":"The cricket paralysis virus (CrPV) intergenic region internal ribosome entry site (IRES) binds to the ribosome without the need for any initiation factors. Their length, simple mechanism, and ability to function in diverse cell-free systems make CrPV-like IRESs useful tools to study the mechanism of translation and to express proteins. We report the use of a RelE-based next-generation sequencing method, termed SMARTI (sequencing-based mutational analysis of RNA translation initiation), to quantitatively determine the function of over 81 000 single and double mutants of CrPV IRES. The result is a comprehensive mutational database that serves as a consensus sequence-like analysis of IRES function. We have given particular attention to the sequence requirements within the three pseudoknots of the IRES element. The data indicate that each pseudoknot contains positions that are modifiable and mutation may even enhance IRES function through pseudotranslocation. CrPV IRES must balance being stable and dynamic as it forms the structure and ribosomal contacts required for translation initiation. Helical regions, especially in the transfer RNA-mimicking domain, are areas where flexibility may be especially beneficial. Moreover, we demonstrated that this high-throughput method is compatible with eukaryotic extract, providing an avenue for studying diverse eukaryotic RNA elements and for engineering sequences for protein expression.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"133 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144146189","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

The mechanism of lineage-specific tRNA recognition by bacterial tryptophanyl-tRNA synthetase and its implications for inhibitor discovery. 细菌色氨酸-tRNA合成酶识别谱系特异性tRNA的机制及其对抑制剂发现的意义。

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-05-22 DOI: 10.1093/nar/gkaf466

Xiaoying Peng, Kaijiang Xia, Lingzhen Xiao, Haoran Qi, Qingting Huang, Manli Xiang, Lu Han, Haipeng Qiu, Qiong Gu, Bingyi Chen, Huihao Zhou

{"title":"The mechanism of lineage-specific tRNA recognition by bacterial tryptophanyl-tRNA synthetase and its implications for inhibitor discovery.","authors":"Xiaoying Peng, Kaijiang Xia, Lingzhen Xiao, Haoran Qi, Qingting Huang, Manli Xiang, Lu Han, Haipeng Qiu, Qiong Gu, Bingyi Chen, Huihao Zhou","doi":"10.1093/nar/gkaf466","DOIUrl":"10.1093/nar/gkaf466","url":null,"abstract":"Tryptophanyl-tRNA synthetase (TrpRS) catalyzes the attachment of tryptophan (l-Trp) to tRNATrp, thereby providing the ribosome with a crucial substrate for the decoding of the UGG codon during protein translation. Both bacterial and eukaryotic TrpRSs are unable to efficiently cross-aminoacylate their respective tRNATrp substrates, indicating the evolution of lineage-specific mechanisms for tRNATrp recognition. Herein, we present the first co-crystal structure of bacterial TrpRS from Escherichia coli (EcTrpRS) in complex with its tRNATrp. EcTrpRS demonstrates bacterial-specific interactions with both the anticodon triplet and the acceptor arm of tRNATrp. Particularly, the bacterial-specific residue Glu155 forms hydrogen bonds with the discriminator base G73, thereby stabilizing it in a conformation distinct from that of A73 in the eukaryotic tRNATrp bound to human TrpRS. Through compound screening, we identified tirabrutinib and its analogues as selective inhibitors of bacterial TrpRS. These compounds occupy the l-Trp and tRNATrp CCA end binding sites of bacterial TrpRS, both of which exhibit less conservation compared to the ATP binding site between bacterial and eukaryotic TrpRSs. These findings enhance our understanding of the lineage-specific recognition of tRNATrp by bacterial TrpRS and highlight the CCA end binding site as a promising target for the future development of selective bacterial TrpRS inhibitors as potential antimicrobials.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 10","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural basis of G-quadruplex recognition by a camelid antibody fragment. 骆驼抗体片段识别g -四重体的结构基础。

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-05-22 DOI: 10.1093/nar/gkaf453

Mojca Pevec, Tadej Medved, Matic Kovačič, Neža Žerjav, Jernej Imperl, Janez Plavec, Jurij Lah, Remy Loris, San Hadži

{"title":"Structural basis of G-quadruplex recognition by a camelid antibody fragment.","authors":"Mojca Pevec, Tadej Medved, Matic Kovačič, Neža Žerjav, Jernej Imperl, Janez Plavec, Jurij Lah, Remy Loris, San Hadži","doi":"10.1093/nar/gkaf453","DOIUrl":"10.1093/nar/gkaf453","url":null,"abstract":"Apart from the iconic Watson-Crick duplex, DNA can fold into different noncanonical structures, of which the most studied are G-quadruplexes (G4s). Despite mounting structural and biophysical evidence, their existence in cells was controversial until their detection using G4-specific antibodies. However, it remains unknown how antibodies recognize G4s at the molecular level and why G4-specific antibodies have low selectivity and are unable to distinguish different G4 sequences. Here, we present the crystal structure of a nanobody bound to the archetypical G4 structure, the thrombin-binding aptamer (TBA). The nanobody exhibits strong selectivity against different G4 sequences and utilizes an unusual scaffold-based paratope, with very limited involvement of complementarity-determining region. The nanobody effectively mimics the binding interface of thrombin, a natural binding partner of TBA, by using isosteric interactions at key positions. The presented structure sheds light on the molecular basis of how antibodies, essential G4-detection tools, recognize noncanonical G4 structures.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 10","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12117401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144160624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Timed chromatin invasion during mitosis governs prototype foamy virus integration site selection and infectivity. 有丝分裂时的定时染色质入侵控制着原型泡沫病毒整合、位点选择和感染性。

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-05-22 DOI: 10.1093/nar/gkaf449

Floriane Lagadec, Parmit K Singh, Christina Calmels, Delphine Lapaillerie, Dirk Lindemann, Vincent Parissi, Peter Cherepanov, Alan N Engelman, Paul Lesbats

{"title":"Timed chromatin invasion during mitosis governs prototype foamy virus integration site selection and infectivity.","authors":"Floriane Lagadec, Parmit K Singh, Christina Calmels, Delphine Lapaillerie, Dirk Lindemann, Vincent Parissi, Peter Cherepanov, Alan N Engelman, Paul Lesbats","doi":"10.1093/nar/gkaf449","DOIUrl":"10.1093/nar/gkaf449","url":null,"abstract":"Selection of a suitable chromatin environment during retroviral integration is a tightly regulated process. Most retroviruses, including spumaretroviruses, require mitosis for nuclear entry. However, whether intrinsic chromatin dynamics during mitosis modulates retroviral genome invasion is unknown. Previous work uncovered critical interactions of prototype foamy virus (PFV) Gag with nucleosomes via a highly conserved arginine anchor residue. Yet, the regulation of Gag-chromatin interaction and its functional consequences for spumaretrovirus biology remain obscure. Here, we investigated the kinetics of chromatin binding by Gag during mitosis and proviral integration in synchronized cells. We showed that alteration of Gag affinity for nucleosome binding induced untimely chromatin tethering during mitosis, decreased infectivity, and redistributed viral integration sites to markers associated with late replication timing of chromosomes. Mutant Gag proteins were, moreover, defective in their ability to displace the histone H4 tail from the nucleosome acidic patch of highly condensed chromatin. These data indicate that the chromatin landscape during Gag-nucleosome interactions is important for PFV integration site selection and that spumaretroviruses evolved high-affinity chromatin binding to overcome early mitosis chromatin condensation.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 10","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A post-assembly conformational change makes the SARS-CoV-2 polymerase elongation-competent. 组装后的构象变化使SARS-CoV-2聚合酶具有延伸能力。

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-05-22 DOI: 10.1093/nar/gkaf450

Misha Klein, Arnab Das, Subhas C Bera, Thomas K Anderson, Dana Kocincova, Hery W Lee, Bing Wang, Flavia S Papini, John C Marecki, Jamie J Arnold, Craig E Cameron, Kevin D Raney, Irina Artsimovitch, Mathias Götte, Robert N Kirchdoerfer, Martin Depken, David Dulin

{"title":"A post-assembly conformational change makes the SARS-CoV-2 polymerase elongation-competent.","authors":"Misha Klein, Arnab Das, Subhas C Bera, Thomas K Anderson, Dana Kocincova, Hery W Lee, Bing Wang, Flavia S Papini, John C Marecki, Jamie J Arnold, Craig E Cameron, Kevin D Raney, Irina Artsimovitch, Mathias Götte, Robert N Kirchdoerfer, Martin Depken, David Dulin","doi":"10.1093/nar/gkaf450","DOIUrl":"10.1093/nar/gkaf450","url":null,"abstract":"Coronaviruses (CoVs) encode 16 nonstructural proteins (nsps), most of which form the replication-transcription complex (RTC). The RTC contains a core composed of one nsp12 RNA-dependent RNA polymerase (RdRp), two nsp8s, and one nsp7. The core RTC recruits other nsps to synthesize all viral RNAs within the infected cell. While essential for viral replication, the mechanism by which the core RTC assembles into a processive polymerase remains poorly understood. We show that the core RTC preferentially assembles by first having nsp12-polymerase bind to the RNA template, followed by the subsequent association of nsp7 and nsp8. Once assembled on the RNA template, the core RTC requires hundreds of seconds to undergo a conformational change that enables processive elongation. In the absence of RNA, the (apo-)RTC requires several hours to adopt its elongation-competent conformation. We propose that this obligatory activation step facilitates the recruitment of additional nsps essential for efficient viral RNA synthesis and may represent a promising target for therapeutic interventions.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 10","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0