Nucleic Acids Research最新文献

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Cancer histone mutations impact protein binding and DNA repair with possible links to genomic instability. 癌症组蛋白突变影响蛋白质结合和DNA修复,可能与基因组不稳定有关。
IF 13.1 2区 生物学
Nucleic Acids Research Pub Date : 2025-09-05 DOI: 10.1093/nar/gkaf899
Daniel Espiritu, Yiru Sheng, Yunhui Peng, Daria Ostroverkhova, Shuxiang Li, David Landsman, Maria J Aristizabal, Anna R Panchenko
{"title":"Cancer histone mutations impact protein binding and DNA repair with possible links to genomic instability.","authors":"Daniel Espiritu, Yiru Sheng, Yunhui Peng, Daria Ostroverkhova, Shuxiang Li, David Landsman, Maria J Aristizabal, Anna R Panchenko","doi":"10.1093/nar/gkaf899","DOIUrl":"10.1093/nar/gkaf899","url":null,"abstract":"<p><p>Histones are key epigenetic factors that regulate the accessibility and compaction of eukaryotic genomes, affecting DNA replication and repair, and gene expression. Recent studies have demonstrated that histone missense mutations can perturb normal histone function, promoting the development of phenotypically distinguishable cancers. However, most histone mutations observed in cancer patients remain enigmatic in their potential to promote cancer development. To assess the oncogenic potential of histone missense mutations, we have gathered whole-exome sequencing data for the tumors of about 12 000 patients. Histone mutations occurred in about 16% of cancer patients, although specific cancer types showed substantially higher rates. Using genomic, structural, and biophysical analyses, we found several predominant modes of action by which histone mutations may alter function. Namely, cancer missense mutations primarily affected histone acidic patch residues and protein-binding interfaces in a cancer-specific manner and targeted interaction interfaces with specific DNA repair proteins. Consistent with this finding, we observed a high tumor mutational burden in patients with histone mutations affecting interactions with proteins involved in maintaining genome integrity. We identified potential cancer driver mutations in several histone genes, including mutations on histone H4-a highly conserved histone without previously documented driver mutations.</p>","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 17","pages":""},"PeriodicalIF":13.1,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086688","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
Decoding the base flipping mechanism of the SET- and RING-associated (SRA) domain of the epigenetic UHRF1 protein. 解码表观遗传UHRF1蛋白的SET- and RING-associated (SRA)结构域的碱基翻转机制。
IF 13.1 2区 生物学
Nucleic Acids Research Pub Date : 2025-09-05 DOI: 10.1093/nar/gkaf909
Dipanjan Mukherjee, Stefano Ciaco, Lara Martinez-Fernandez, Krishna Gavvala, Elisa Bombarda, Aurélie Bourdérioux, Dmytro Dziuba, Fabien Hanser, Nicolas Humbert, Aqib Javed, Marc Mousli, Pankhi Singh, Yitzhak Tor, Roberto Improta, Mattia Mori, Yves Mély
{"title":"Decoding the base flipping mechanism of the SET- and RING-associated (SRA) domain of the epigenetic UHRF1 protein.","authors":"Dipanjan Mukherjee, Stefano Ciaco, Lara Martinez-Fernandez, Krishna Gavvala, Elisa Bombarda, Aurélie Bourdérioux, Dmytro Dziuba, Fabien Hanser, Nicolas Humbert, Aqib Javed, Marc Mousli, Pankhi Singh, Yitzhak Tor, Roberto Improta, Mattia Mori, Yves Mély","doi":"10.1093/nar/gkaf909","DOIUrl":"10.1093/nar/gkaf909","url":null,"abstract":"<p><p>Ubiquitin-like, containing PHD and RING fingers domains 1 (UHRF1) plays a pivotal role in replicating DNA methylation patterns during cell division. Acting as a DNA reader, UHRF1, via its SET- and RING-associated (SRA) domain, recognizes hemi-methylated (HM) CpG sites and flips 5-methylcytosine (5mC) nucleobases. This flipping triggers DNA methyltransferase 1 (DNMT1) recruitment to methylate cytosine in the complementary strand. To investigate the SRA-induced base-flipping mechanism, we introduced thienoguanosine (thG), a fluorescent guanosine analogue, at four positions in HM and non-methylated duplexes. The interactions of these labelled duplexes with wild-type SRA and a G448D mutant (incapable of base-flipping) were monitored using a combination of stopped-flow fluorescence measurements, molecular dynamics simulations, and quantum mechanical calculations. We show that 5mC and C residues are flipped with similar rate constants. However, while C residues rapidly revert to their original state, enabling SRA to continue reading or dissociate, SRA complexes with flipped 5mC undergo a slow conformational rearrangement, leading to the final conformation crucial for DNMT1 recruitment. Taken together, our findings suggest that base flipping is used to discriminate 5mC from C residues, while the ensuing conformational rearrangement drives DNMT1 recruitment.</p>","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 17","pages":""},"PeriodicalIF":13.1,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086709","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
Machine learning-based analysis of the impact of 5' untranslated region on protein expression. 基于机器学习的5'非翻译区对蛋白表达影响分析。
IF 14.9 2区 生物学
Nucleic Acids Research Pub Date : 2025-09-05 DOI: 10.1093/nar/gkaf861
Linfeng Wang,Sujia Liu,Jia-Xin Huang,Haifeng Zhu,Shuyu Li,Yannan Li,Sen Chen,Jianying Han,Yin Zhu,Jiahao Wu,Wentao Liao,Hongmei Zhang,Haiyan Zeng,Shaoting Li,Shuping Zhao,Bingwei Wang,Jiaqi Lin,Ji Zeng
{"title":"Machine learning-based analysis of the impact of 5' untranslated region on protein expression.","authors":"Linfeng Wang,Sujia Liu,Jia-Xin Huang,Haifeng Zhu,Shuyu Li,Yannan Li,Sen Chen,Jianying Han,Yin Zhu,Jiahao Wu,Wentao Liao,Hongmei Zhang,Haiyan Zeng,Shaoting Li,Shuping Zhao,Bingwei Wang,Jiaqi Lin,Ji Zeng","doi":"10.1093/nar/gkaf861","DOIUrl":"https://doi.org/10.1093/nar/gkaf861","url":null,"abstract":"The 5' untranslated region (5'UTR) plays a crucial regulatory role in messenger RNA (mRNA), with modified 5'UTRs extensively utilized in vaccine production, gene therapy, etc. Nevertheless, manually optimizing 5'UTRs may encounter difficulties in balancing the effects of various cis-elements. Consequently, multiple 5'UTR libraries have been created, and machine learning models have been employed to analyze and predict translation efficiency (TE) and protein expression, providing insights into critical regulatory features. On the one hand, these screening libraries, based on TE and mean ribosome load, struggle to accurately quantify protein expression; on the other hand, a precise method for quantifying 5'UTRs necessitates a significantly costlier library. To resolve this dilemma, we constructed a library utilizing firefly luciferase as the reporter to measure accurate protein expression. In addition, we optimized the library construction method by clustering mRNA sequences to reduce redundant data and minimize the size of the dataset. This dual strategy by increasing accuracy and reducing dataset size was found to be effective in predicting the 5'UTRs from the PC3 cell line.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"307 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018264","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
DDX6 interacts with DDX3X to repress translation in microRNA-mediated silencing. DDX6与DDX3X相互作用抑制microrna介导的沉默中的翻译。
IF 14.9 2区 生物学
Nucleic Acids Research Pub Date : 2025-09-05 DOI: 10.1093/nar/gkaf868
Yanyan Lu,Meng Tao,Hong Su,Yiren Tu,Ji-Ping Wang,Masahiko Kuroda,Xiaozhong Wang
{"title":"DDX6 interacts with DDX3X to repress translation in microRNA-mediated silencing.","authors":"Yanyan Lu,Meng Tao,Hong Su,Yiren Tu,Ji-Ping Wang,Masahiko Kuroda,Xiaozhong Wang","doi":"10.1093/nar/gkaf868","DOIUrl":"https://doi.org/10.1093/nar/gkaf868","url":null,"abstract":"DDX6 is known to repress messenger RNA (mRNA) translation and promote mRNA decay in microRNA-mediated silencing. In embryonic stem cells (ESCs), DDX6 primarily functions at the translation level, independent of mRNA destabilization; however, the precise molecular mechanism of how DDX6 represses translation remains unclear. Here, we identify DDX3X as a key downstream target of DDX6-mediated translational repression in ESCs. Conditional knockout of DDX3X demonstrates its essential role in microRNA (miRNA) silencing. Biochemical analyses reveal that DDX6 directly binds to DDX3X, with the C-terminal region of DDX6 being necessary for this interaction. ESCs lacking DDX6 and rescued with a DDX6 mutant that is defective in DDX3X interaction continue to exhibit miRNA silencing defects. Furthermore, the mutant DDX6 is unable to inhibit 48S preinitiation complex formation in vitro. These findings uncover a novel mechanism in which DDX6 represses target mRNA translation via its interaction with DDX3X.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"15 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018265","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
Toward standardized epitranscriptome analytics: an inter-laboratory comparison of mass spectrometric detection and quantification of modified ribonucleosides in human RNA. 迈向标准化的表转录组分析:人类RNA中修饰核糖核苷的质谱检测和定量的实验室间比较。
IF 13.1 2区 生物学
Nucleic Acids Research Pub Date : 2025-09-05 DOI: 10.1093/nar/gkaf895
Martin Hengesbach, Chi-Kong Chan, Tulsi Bhandari, Alan Bruzel, Michael S DeMott, Ganna Podoprygorina, Guangxin Sun, Ellen Tabeling, Vivian G Cheung, Peter C Dedon, Mark Helm, Patrick A Limbach
{"title":"Toward standardized epitranscriptome analytics: an inter-laboratory comparison of mass spectrometric detection and quantification of modified ribonucleosides in human RNA.","authors":"Martin Hengesbach, Chi-Kong Chan, Tulsi Bhandari, Alan Bruzel, Michael S DeMott, Ganna Podoprygorina, Guangxin Sun, Ellen Tabeling, Vivian G Cheung, Peter C Dedon, Mark Helm, Patrick A Limbach","doi":"10.1093/nar/gkaf895","DOIUrl":"10.1093/nar/gkaf895","url":null,"abstract":"<p><p>The human RNome comprises all forms of RNA and the 50 + chemical structures-the epitranscriptome-that modify them. Understanding the diverse functions of RNA modifications in regulating gene expression and cell phenotype requires technologies such as RNA sequencing-based modification mapping and mass spectrometry-based quantification of modified ribonucleosides. Liquid chromatography-coupled tandem quadrupole mass spectrometry (LC-MS/MS) is the gold standard for detecting and quantifying modified ribonucleosides with accuracy and precision. However, variations in RNA isolation, processing, and LC-MS/MS analysis have hindered reproducibility across laboratories, which is essential for accurate quantification of RNA modifications. As guidance toward harmonization, we report a multi-laboratory comparison of workflows for LC-MS/MS RNA modification analysis. We compared protocols for sample shipment, RNA hydrolysis, LC-MS/MS analysis, and data processing among three laboratories working with the same total RNA samples. We detected and quantified 17 modifications consistently across protocols and operators, with another 7 that were sensitive to experimental conditions, reagent contamination, and ribonucleoside instability, leading to poor precision among laboratories. Agreement among the three labs was strong, with coefficients of variation of 20% and 10% for relative and absolute quantification, respectively. These findings establish a robust and readily adoptable epitranscriptome analytical platform that enables reliable comparisons across laboratories.</p>","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 17","pages":""},"PeriodicalIF":13.1,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12445667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086796","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
Moss BRCA2 lacking the canonical DNA-binding domain promotes homologous recombination and binds to DNA. 缺乏典型DNA结合域的苔藓BRCA2促进同源重组并与DNA结合。
IF 14.9 2区 生物学
Nucleic Acids Research Pub Date : 2025-09-05 DOI: 10.1093/nar/gkaf856
Alice Chanteau,Suliane Quilleré,Arthur Crouset,Sreejith Allipra,Ulysse Tuquoi,Pierre-François Perroud,Simona Miron,Pauline Dupaigne,Sophie Zinn-Justin,Fabien Nogué,Rajeev Kumar
{"title":"Moss BRCA2 lacking the canonical DNA-binding domain promotes homologous recombination and binds to DNA.","authors":"Alice Chanteau,Suliane Quilleré,Arthur Crouset,Sreejith Allipra,Ulysse Tuquoi,Pierre-François Perroud,Simona Miron,Pauline Dupaigne,Sophie Zinn-Justin,Fabien Nogué,Rajeev Kumar","doi":"10.1093/nar/gkaf856","DOIUrl":"https://doi.org/10.1093/nar/gkaf856","url":null,"abstract":"BRCA2 is crucial for mediating homology-directed DNA repair (HDR) through its binding to single-stranded DNA (ssDNA) and the recombinases RAD51 and DMC1. Most BRCA2 orthologs have a canonical DNA-binding domain (DBD) with the exception of Drosophila melanogaster. It remains unclear whether such a noncanonical BRCA2 variant without DBD possesses a DNA-binding activity. Here, we identify a new noncanonical BRCA2 in the model plant Physcomitrium patens (PpBRCA2). We establish that PpBRCA2 is essential for genome integrity maintenance, somatic DNA double-strand break (DSB) repair, HDR-mediated gene targeting, and RAD51 foci recruitment at DNA break sites. PpBRCA2 is also critical for DSB repair during meiosis. Interestingly, PpBRCA2 interacts strongly with RAD51 but weakly with DMC1, suggesting a distinct meiotic function compared to other BRCA2 homologs. Despite lacking the canonical DBD, PpBRCA2 binds ssDNA through its disordered N-terminal region and efficiently promotes HDR. Our work highlights that the ssDNA binding capacity of BRCA2 homologs is conserved regardless of the presence of a canonical DBD and provides a deeper understanding of BRCA2's functional diversity across species.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"130 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018150","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
Correction to 'RIG-I recognizes metabolite-capped RNAs as signaling ligands'. 更正“RIG-I识别代谢物限制的rna作为信号配体”。
IF 13.1 2区 生物学
Nucleic Acids Research Pub Date : 2025-09-05 DOI: 10.1093/nar/gkaf933
{"title":"Correction to 'RIG-I recognizes metabolite-capped RNAs as signaling ligands'.","authors":"","doi":"10.1093/nar/gkaf933","DOIUrl":"10.1093/nar/gkaf933","url":null,"abstract":"","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 17","pages":""},"PeriodicalIF":13.1,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12445644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086731","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
The nuclear pore complex acts as a hub for pri-miRNA transcription and processing in plants. 核孔复合物在植物中作为pri-miRNA转录和加工的枢纽。
IF 13.1 2区 生物学
Nucleic Acids Research Pub Date : 2025-09-05 DOI: 10.1093/nar/gkaf885
Lucia Gonzalo, Delfina Gagliardi, Camila Zlauvinen, Tomasz Gulanicz, Agustín L Arce, Josefina Fernandez, Damian A Cambiagno, Catharina Merchante, Agnieszka Zienkiewicz, Artur Jarmolowski, Pablo A Manavella
{"title":"The nuclear pore complex acts as a hub for pri-miRNA transcription and processing in plants.","authors":"Lucia Gonzalo, Delfina Gagliardi, Camila Zlauvinen, Tomasz Gulanicz, Agustín L Arce, Josefina Fernandez, Damian A Cambiagno, Catharina Merchante, Agnieszka Zienkiewicz, Artur Jarmolowski, Pablo A Manavella","doi":"10.1093/nar/gkaf885","DOIUrl":"10.1093/nar/gkaf885","url":null,"abstract":"<p><p>The regulation of miRNA biogenesis and movement is essential for plant development and environmental responses. HASTY (HST), a karyopherin protein, has been implicated in miRNA biogenesis and movement, though its role in non-cell-autonomous miRNA movement remains unclear. Through a genetic screen, we identified that mutations in the HAWAIIAN SKIRT (HWS) gene suppress the developmental defects of hst mutants by restoring miRNA movement. Our findings show that HWS interacts with nuclear transport factors and nuclear pore complex (NPC) components, including NUP1, positioning HWS as a regulator of miRNA nuclear export. Using microscopy and fluorescence in situ hybridization, we showed that pri-miRNA transcription, and likely their co-transcriptional processing, occur at the nuclear pore. Notably, we uncovered an antagonistic relationship between HST and HWS in regulating MIRNA transcription at the NPC and AGO1 loading, which could explain the observed changes in miRNA movement. HST promotes the association of MIRNA loci with the NPC, spatially positioning co-transcriptional processing by the NPC. Conversely, HWS negatively regulates this process by degrading MEDIATOR 37 subunits and detaching the processing complex from the NPC. Our data provide evidence of spatial coordination of miRNA transcription, biogenesis, and movement, highlighting a novel role for the NPC in the miRNA pathway.</p>","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 17","pages":""},"PeriodicalIF":13.1,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086872","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 simple, fast, and cost-efficient protocol for ultra-sensitive ribosome profiling. 一种简单、快速、经济高效的超灵敏核糖体分析方案。
IF 13.1 2区 生物学
Nucleic Acids Research Pub Date : 2025-09-05 DOI: 10.1093/nar/gkaf902
Jiří Koubek, Katharina Jetzinger, Shiran Dror, Mikel Irastortza-Olaziregi, Dana Frank, Ilgin Kotan, Jaime Santos, Frank Tippmann, Pascal Lafrenz, Henrik Kaessmann, Orna Amster-Choder, Bernd Bukau, Günter Kramer
{"title":"A simple, fast, and cost-efficient protocol for ultra-sensitive ribosome profiling.","authors":"Jiří Koubek, Katharina Jetzinger, Shiran Dror, Mikel Irastortza-Olaziregi, Dana Frank, Ilgin Kotan, Jaime Santos, Frank Tippmann, Pascal Lafrenz, Henrik Kaessmann, Orna Amster-Choder, Bernd Bukau, Günter Kramer","doi":"10.1093/nar/gkaf902","DOIUrl":"10.1093/nar/gkaf902","url":null,"abstract":"<p><p>Ribosome profiling has become an essential tool for studying messenger RNA (mRNA) translation in cells with codon-level resolution. However, its widespread application remains hindered by the labour-intensive workflow, low efficiency, and high costs associated with sequencing sample preparation. Here, we present a new cost-effective and ultra-sensitive library preparation method that significantly advances the applicability of ribosome profiling. By implementing bead-coupled enzymatic reactions and product purifications, our approach increases both yield and throughput while maintaining high reproducibility. Demonstrating the sensitivity of the protocol, we prepared libraries from as little as 12 fmol of RNA, which expands the feasibility of ribosome profiling from minimal input samples, such as those derived from small populations, stressed cells, or patient-derived specimens. Additionally, we validate the versatility of the protocol across multiple species and demonstrate its applicability for RNA-seq library preparation. Altogether, this protocol provides a highly accessible and efficient alternative to existing ribosome profiling workflows, facilitating research in previously challenging experimental contexts.</p>","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 17","pages":""},"PeriodicalIF":13.1,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086677","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
Mutations on the surface of HDAC1 reveal molecular determinants of specific complex assembly and their requirement for gene regulation. HDAC1表面的突变揭示了特定复合物组装的分子决定因素及其对基因调控的要求。
IF 13.1 2区 生物学
Nucleic Acids Research Pub Date : 2025-09-05 DOI: 10.1093/nar/gkaf918
Ahmad Alshehri, India-May Baker, David M English, Louise Fairall, Mark O Collins, John W R Schwabe, Shaun M Cowley
{"title":"Mutations on the surface of HDAC1 reveal molecular determinants of specific complex assembly and their requirement for gene regulation.","authors":"Ahmad Alshehri, India-May Baker, David M English, Louise Fairall, Mark O Collins, John W R Schwabe, Shaun M Cowley","doi":"10.1093/nar/gkaf918","DOIUrl":"10.1093/nar/gkaf918","url":null,"abstract":"<p><p>Histone deacetylase 1 and 2 (HDAC1/2) regulate histone acetylation as catalytic and structural components of six unique multiprotein complex families: SIN3, NuRD, CoREST, MIDAC, MIER, and RERE. Co-immunoprecipitation of HDAC1-Flag followed by mass spectrometry revealed that 92% of HDAC1 in mouse embryonic stem cells resides in three complexes, NuRD (49%), CoREST (28%), and SIN3 (15%). We compared the structures of MTA1:HDAC1 and MIDEAS:HDAC1 to identify critical binding residues on the surface of HDAC1. Surprisingly, a single mutation, Y48E, disrupts binding to all complexes except SIN3. Rescue experiments performed with HDAC1-Y48E in HDAC1/2 double-knockout cells showed that retention of SIN3 binding alone is sufficient for cell viability. Gene expression and histone acetylation patterns were perturbed in both Y48E and a second mutant cell line, HDAC1-E63R, indicating that cells require a full repertoire of the HDAC1/2 complexes to regulate their transcriptome appropriately. Comparative analysis of MTA1/HDAC1 and SIN3B/HDAC2 structures confirmed the differential modes of HDAC1 recruitment, with Y48 interacting with ELM2/SANT domain-containing proteins, but not SIN3. The E63R mutation shows markedly reduced binding to NuRD and MiDAC complexes but retains some CoREST binding. We provide novel molecular insights into the abundance, co-factors and assemblies of this crucial family of chromatin modifying machines.</p>","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 17","pages":""},"PeriodicalIF":13.1,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086788","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
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