Nucleic Acids Research最新文献

Screening of metallohelices for enantioselective targeting SARS-CoV-2 RNA G-quadruplex 靶向SARS-CoV-2 RNA g -四联体金属螺旋的筛选

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-05-31 DOI: 10.1093/nar/gkaf199

Yue Sun, Chuanqi Zhao, Yan Liu, Yibo Wang, Cheng Zhang, Jie Yang, Geng Qin, Hualong Song, Miles Postings, Peter Scott, Jinsong Ren, Xiaogang Qu

{"title":"Screening of metallohelices for enantioselective targeting SARS-CoV-2 RNA G-quadruplex","authors":"Yue Sun, Chuanqi Zhao, Yan Liu, Yibo Wang, Cheng Zhang, Jie Yang, Geng Qin, Hualong Song, Miles Postings, Peter Scott, Jinsong Ren, Xiaogang Qu","doi":"10.1093/nar/gkaf199","DOIUrl":"https://doi.org/10.1093/nar/gkaf199","url":null,"abstract":"The emergence of numerous variants of SARS-CoV-2 still presents the major challenges in the fight against this disease by reducing the efficacy of vaccines and drugs. RNA G-quadruplexes (G4s) in the SARS-CoV-2 genome are highly conserved and have thus been spotlighted as a promising therapeutic target to combat a wider range of variants. However, very few RNA G4 specific compounds have been reported. Here, a small library of 64 chiral metallohelices has been constructed for screening SARS-CoV-2 G4-specific binders. After screening, we found that one pair of the enantiomers showed the best enantioselectivity. The Λ enantiomer can strongly stabilize SARS-CoV-2 G4s, inhibit the expression of virus protein, and reduce the SARS-CoV-2 RNA copies and viral titers in Vero E6 cells. In contrast, the Δ enantiomer has much weaker effects than the Λ enantiomer under the same experimental conditions, showing an obvious enantioselectivity. Further studies indicate that the Λ enantiomer prefers binding to SARS-CoV-2 G4s rather than binding to the single/double-stranded DNA and commonly reported human DNA G4s, indicating its selectivity to RNA G4s. This work provides the first example for enantioselectively targeting SARS-CoV-2 G4s, and will promote developing drug candidates for targeting virus G4s.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"50 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144188865","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

Structural studies of ribosome from an anaerobic Bacteroidetes human pathogen Porphyromonas gingivalis 厌氧拟杆菌门人类病原体牙龈卟啉单胞菌核糖体的结构研究

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-05-30 DOI: 10.1093/nar/gkaf458

Disha-Gajanan Hiregange, Sarit Samiya, Danuta Mizgalska, Efrat Ben-Zeev, Miriam Waghalter, Andre Rivalta, K Shanmugha Rajan, Yehuda Halfon, Elinor Breiner-Goldstein, Igor Kaczmarczyk, Aneta Sroka, Masato Taoka, Yuko Nobe, Toshiaki Isobe, Susanne Paukner, Ella Zimmerman, Anat Bashan, Jan Potempa, Ada Yonath

{"title":"Structural studies of ribosome from an anaerobic Bacteroidetes human pathogen Porphyromonas gingivalis","authors":"Disha-Gajanan Hiregange, Sarit Samiya, Danuta Mizgalska, Efrat Ben-Zeev, Miriam Waghalter, Andre Rivalta, K Shanmugha Rajan, Yehuda Halfon, Elinor Breiner-Goldstein, Igor Kaczmarczyk, Aneta Sroka, Masato Taoka, Yuko Nobe, Toshiaki Isobe, Susanne Paukner, Ella Zimmerman, Anat Bashan, Jan Potempa, Ada Yonath","doi":"10.1093/nar/gkaf458","DOIUrl":"https://doi.org/10.1093/nar/gkaf458","url":null,"abstract":"Porphyromonas gingivalis, an anaerobic pathogen in chronic periodontitis, belongs to the Bacteroidota phylum and is associated with various virulence factors. Its antibiotic-resistant strains and its propensity to form biofilms pose a challenge to effective treatment. To explore therapeutic avenues, we studied the high-resolution cryogenic electron microscope structures of ribosomes from the wild-type P. gingivalis W83 and the macrolide-resistant mutant strain ermΔporN. The structural analysis revealed unique features primarily at the ribosome periphery. Together with the distinctive distribution of ribosomal RNA modifications, these findings offer insights into the therapeutical potential, such as creation of novel therapeutic compounds inhibiting the specific cellular functions of the P. gingivalis ribosomes. Moreover, the high-resolution structure of the ermΔporN ribosome in its complex with the approved antibiotic lefamulin suggests its repurposing against P. gingivalis. Furthermore, we provide a foundation for additional effective strategies to treat periodontitis and associated systemic diseases.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"61 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144184119","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

DNMT3A-dependent DNA methylation shapes the endothelial enhancer landscape dnmt3a依赖性DNA甲基化塑造内皮增强子景观

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-05-30 DOI: 10.1093/nar/gkaf435

Stephanie Gehrs, Zuguang Gu, Joschka Hey, Dieter Weichenhan, Niklas Buckwalter, Moritz Jakab, Agnes Hotz-Wagenblatt, Kersten Breuer, Maria Llamazares Prada, Daniel Hübschmann, Katharina Schlereth, Christoph Plass, Hellmut Augustin

{"title":"DNMT3A-dependent DNA methylation shapes the endothelial enhancer landscape","authors":"Stephanie Gehrs, Zuguang Gu, Joschka Hey, Dieter Weichenhan, Niklas Buckwalter, Moritz Jakab, Agnes Hotz-Wagenblatt, Kersten Breuer, Maria Llamazares Prada, Daniel Hübschmann, Katharina Schlereth, Christoph Plass, Hellmut Augustin","doi":"10.1093/nar/gkaf435","DOIUrl":"https://doi.org/10.1093/nar/gkaf435","url":null,"abstract":"DNA methylation plays a fundamental role in regulating transcription during development and differentiation. However, its functional role in the regulation of endothelial cell (EC) transcription during state transition, meaning the switch from an angiogenic to a quiescent cell state, has not been systematically studied. Here, we report the longitudinal changes of the DNA methylome over the lifetime of the murine pulmonary vasculature. We identified prominent alterations in hyper- and hypomethylation during the transition from angiogenic to quiescent ECs. Once a quiescent state was established, DNA methylation marks remained stable throughout EC aging. These longitudinal differentially methylated regions correlated with endothelial gene expression and highlighted the recruitment of de novo DNA methyltransferase 3a (DNMT3A), evidenced by its motif enrichment at transcriptional start sites of genes with methylation-dependent expression patterns. Loss-of-function studies in mice revealed that the absence of DNMT3A-dependent DNA methylation led to the loss of active enhancers, resulting in mild transcriptional changes, likely due to loss of active enhancer integrity. These results underline the importance of DNA methylation as a key epigenetic mechanism of EC function during state transition. Furthermore, we show that DNMT3A-dependent DNA methylation appears to be involved in establishing the histone landscape required for accurate transcriptome regulation.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"134 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176578","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

Improved DNA binding to a type IV minor pilin increases natural transformation 改良的DNA与IV型小蛋白的结合增加了自然转化

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-05-30 DOI: 10.1093/nar/gkaf467

Taylor J Ellison, Courtney K Ellison

引用次数: 0

Structural insight into the novel Thermus thermophilus SPOUT methyltransferase RlmR catalysing Um2552 formation in the 23S rRNA A-loop: a case of convergent evolution 在23S rRNA a环中催化Um2552形成的新型Thermus thermoophilus SPOUT甲基转移酶RlmR的结构洞察：趋同进化的一个案例

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-05-30 DOI: 10.1093/nar/gkaf432

Yousra Tanouti, Martine Roovers, Philippe Wolff, Antony Lechner, Dany Van Elder, André Feller, Romuald Soin, Cyril Gueydan, Véronique Kruys, Louis Droogmans, Geoffray Labar

{"title":"Structural insight into the novel Thermus thermophilus SPOUT methyltransferase RlmR catalysing Um2552 formation in the 23S rRNA A-loop: a case of convergent evolution","authors":"Yousra Tanouti, Martine Roovers, Philippe Wolff, Antony Lechner, Dany Van Elder, André Feller, Romuald Soin, Cyril Gueydan, Véronique Kruys, Louis Droogmans, Geoffray Labar","doi":"10.1093/nar/gkaf432","DOIUrl":"https://doi.org/10.1093/nar/gkaf432","url":null,"abstract":"The A-loop of the 23S ribosomal RNA is a critical region of the ribosome involved in stabilizing the CCA-end of A-site-bound transfer RNA. Within this loop, nucleotide U2552 is frequently 2′-O-methylated (Um2552) in various organisms belonging to the three domains of life. Until now, two enzymatic systems are known to modify this position, relying on either a Rossmann fold-like methyltransferase (RFM) or a small RNA-guided system. Here, we report the identification of a third system involved in Um2552 formation, consisting of a methyltransferase of the SPOUT (SpoU-TrmD) superfamily encoded by the ttc1712 open reading frame of Thermus thermophilus, herein renamed RlmR. In Escherichia coli and human mitochondria, the absence of the RFM enzyme responsible for Um2552 formation is known to cause severe defects in ribogenesis and ribosome function. In contrast, no comparable effect was observed upon ttc1712 gene invalidation in T. thermophilus. We also report the high-resolution crystal structure of RlmR in complex with a 59-mer substrate RNA. The structure highlights significant conformational rearrangements of the A-loop and provides a new insight into the catalytic mechanism, revealing structural features that may be generalized to other SpoU methyltransferases.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"8 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176647","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

RNA-binding protein Ars2 mediates transcriptional silencing of telomeric repeats and transposable elements in the Drosophila germline rna结合蛋白Ars2介导果蝇种系中端粒重复序列和转座因子的转录沉默

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-05-30 DOI: 10.1093/nar/gkaf486

Valeriya Morgunova, Anastasiya A Kobelyatskaya, Maksim Erokhin, Olesya Sokolova, Tatyana V Sizova, Dmitry A Kwon, Alla Kalmykova

{"title":"RNA-binding protein Ars2 mediates transcriptional silencing of telomeric repeats and transposable elements in the Drosophila germline","authors":"Valeriya Morgunova, Anastasiya A Kobelyatskaya, Maksim Erokhin, Olesya Sokolova, Tatyana V Sizova, Dmitry A Kwon, Alla Kalmykova","doi":"10.1093/nar/gkaf486","DOIUrl":"https://doi.org/10.1093/nar/gkaf486","url":null,"abstract":"Telomeres ensure genome stability and the levels of telomeric RNA reflect the integrity of telomeric chromatin. The highly conserved RNA-binding protein Ars2 (Arsenite-resistance protein 2) plays an essential role in the RNA nuclear metabolism and negatively regulates the expression of telomeric transcripts in human cells and in Drosophila. We found that germline knockdown of Drosophila Ars2 does not affect small RNA abundance but causes overexpression of telomeric repeats and transposable elements (TEs), accompanied by chromatin decompaction of these regions. The expression of a transgene containing the HeT-A telomeric retrotransposon was also affected by Ars2 knockdown. The mutation of the G-rich region, which is prone to the formation of G-quadruplex structures, reduces the HeT-A transgene’s sensitivity to Ars2 depletion. Intriguingly, Ars2-regulated non-telomeric TEs are also enriched by G-quadruplex structures, implying their role in the Ars2 target recognition. Ars2 also prevents the formation of R-loops at telomeres, which are most likely caused by the accumulation of unreleased transcripts. Surprisingly, Ars2 is required for the expression of R1 retrotransposons, which are integrated in rRNA genes and essential for their amplification. Our findings point to a new mechanism for control of expression of telomeric repeats and TEs in the germline involving Ars2.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"19 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176602","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

RecN and RecA orchestrate an ordered DNA supercompaction response following ciprofloxacin-induced DNA damage in Escherichia coli 在环丙沙星诱导的大肠杆菌DNA损伤后，RecN和RecA协调有序的DNA超压缩反应

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-05-28 DOI: 10.1093/nar/gkaf437

Krister Vikedal, Synnøve Brandt Ræder, Ida Mathilde Marstein Riisnæs, Magnar Bjørås, James Alexander Booth, Kirsten Skarstad, Emily Helgesen

{"title":"RecN and RecA orchestrate an ordered DNA supercompaction response following ciprofloxacin-induced DNA damage in Escherichia coli","authors":"Krister Vikedal, Synnøve Brandt Ræder, Ida Mathilde Marstein Riisnæs, Magnar Bjørås, James Alexander Booth, Kirsten Skarstad, Emily Helgesen","doi":"10.1093/nar/gkaf437","DOIUrl":"https://doi.org/10.1093/nar/gkaf437","url":null,"abstract":"Fluoroquinolones induce double-strand breaks in bacterial DNA, triggering the SOS response, a major DNA damage response that ensures the expression of repair proteins but also promotes the emergence and spread of antibiotic resistance. Fluoroquinolone resistance, particularly in Escherichia coli, is a growing global health concern. Understanding bacterial responses to these antibiotics is critical for developing preventive strategies and novel treatments to combat resistance development. This study investigates DNA morphology in E. coli following exposure to ciprofloxacin (CIP), a fluoroquinolone antibiotic. We show that CIP induces a stepwise DNA reorganization, culminating in a highly dense nucleoid structure at midcell—a process we term DNA supercompaction. This phenomenon occurred also with other genotoxic agents. Live-cell imaging revealed that RecN, a structural maintenance of chromosomes (SMC)-like protein, is required for DNA supercompaction, and that RecN’s dynamics and activity in this response depend on RecA. Additionally, RecN and RecA frequently colocalized at nucleoid-associated positions. We suggest that RecN and RecA play active roles in DNA supercompaction following severe DNA damage, that their interplay is part of a prompt universal survival response to DNA double-strand breaks in E. coli, and that the extent of the compaction response depends on the DNA damage severity.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"152 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153387","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

SCIG: Machine learning uncovers cell identity genes in single cells by genetic sequence codes SCIG：机器学习通过基因序列密码揭示单细胞中的细胞识别基因

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-05-28 DOI: 10.1093/nar/gkaf431

Kulandaisamy Arulsamy, Bo Xia, Yang Yu, Hong Chen, William T Pu, Lili Zhang, Kaifu Chen

{"title":"SCIG: Machine learning uncovers cell identity genes in single cells by genetic sequence codes","authors":"Kulandaisamy Arulsamy, Bo Xia, Yang Yu, Hong Chen, William T Pu, Lili Zhang, Kaifu Chen","doi":"10.1093/nar/gkaf431","DOIUrl":"https://doi.org/10.1093/nar/gkaf431","url":null,"abstract":"Deciphering cell identity genes is pivotal to understanding cell differentiation, development, and cell identity dysregulation involving diseases. Here, we introduce SCIG, a machine-learning method to uncover cell identity genes in single cells. In alignment with recent reports that cell identity genes (CIGs) are regulated with unique epigenetic signatures, we found CIGs exhibit distinctive genetic sequence signatures, e.g. unique enrichment patterns of cis-regulatory elements. Using these genetic sequence signatures, along with gene expression information from single-cell RNA-seq data, SCIG uncovers the identity genes of a cell without a need for comparison to other cells. CIG score defined by SCIG surpassed expression value in network analysis to reveal the master transcription factors (TFs) regulating cell identity. Applying SCIG to the human endothelial cell atlas revealed that the tissue microenvironment is a critical supplement to master TFs for cell identity refinement. SCIG is publicly available at https://doi.org/10.5281/zenodo.14726426 , offering a valuable tool for advancing cell differentiation, development, and regenerative medicine research.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"45 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153386","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 conserved nuclease facilitates environmental DNA uptake 一个保守的核酸酶促进环境DNA的摄取

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-05-27 DOI: 10.1093/nar/gkaf443

Juri Hanßmann, Jan Pané-Farré, Milena Meiser, Mathias Girbig, Lifei Fu, M Gregor Madej, Franziska L Sendker, Clemens Thölken, Marcus Lechner, Christine Ziegler, Georg K A Hochberg, Gert Bange, Martin Thanbichler, Rebecca Hinrichs

{"title":"A conserved nuclease facilitates environmental DNA uptake","authors":"Juri Hanßmann, Jan Pané-Farré, Milena Meiser, Mathias Girbig, Lifei Fu, M Gregor Madej, Franziska L Sendker, Clemens Thölken, Marcus Lechner, Christine Ziegler, Georg K A Hochberg, Gert Bange, Martin Thanbichler, Rebecca Hinrichs","doi":"10.1093/nar/gkaf443","DOIUrl":"https://doi.org/10.1093/nar/gkaf443","url":null,"abstract":"Bacteria acquire new traits through the uptake of genetic material from the environment, a process requiring DNA processing. However, the molecular inventory mediating this process is far from being completely understood. Here, we identify YhaM in Bacillus subtilis as a conserved 3′-deoxyribonuclease essential for the uptake and processing of genetic information in the form of single-stranded DNA. Our results show that YhaM assembles into hexamers in the presence of divalent cations, enhancing substrate binding, which is achieved through its conserved oligonucleotide-binding domain. Cells lacking YhaM show a severe defect in the uptake of plasmids and genomic DNA, but the transduction of double-stranded DNA by the phage SPP1 remains unaffected. These findings highlight a critical role of YhaM in single-stranded DNA maturation during natural transformation. Importantly, this function is conserved in various Gram-positive human pathogens such as Staphylococcus aureus, suggesting that it could contribute to the spread of antibiotic resistance.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"7 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145492","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 role of multivalency in the association of the eight twenty-one protein 2 (ETO2) with the nucleosome remodeling and deacetylase (NuRD) complex 多价性在821蛋白2 （ETO2）与核小体重塑和去乙酰化酶（NuRD）复合体的关联中的作用

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2025-05-27 DOI: 10.1093/nar/gkaf439

Glory Dan-Dukor, Shengzhe Shang, Gage O Leighton, Christopher R Travis, Timothy D Schwochert, Parnika Agrawal, Oyindamola Ajasa, Torry Li, Marcey L Waters, Gordon D Ginder, David C Williams

{"title":"The role of multivalency in the association of the eight twenty-one protein 2 (ETO2) with the nucleosome remodeling and deacetylase (NuRD) complex","authors":"Glory Dan-Dukor, Shengzhe Shang, Gage O Leighton, Christopher R Travis, Timothy D Schwochert, Parnika Agrawal, Oyindamola Ajasa, Torry Li, Marcey L Waters, Gordon D Ginder, David C Williams","doi":"10.1093/nar/gkaf439","DOIUrl":"https://doi.org/10.1093/nar/gkaf439","url":null,"abstract":"Over the past 50 years, research has uncovered the co-regulatory proteins and complexes that silence the expression of the γ-globin gene in a developmental stage-specific manner. Recent research expanded the list of these regulatory factors by showing that the eight twenty-one protein 2 (ETO2) helps recruit the nucleosome remodeling and deacetylase (NuRD) complex to the globin locus. Furthermore, ETO2 regulates hematopoietic differentiation and is a potential therapeutic target for acute leukemia. In this work, we identify critical interactions between ETO2 and the GATA Zn finger domain containing the 2A (GATAD2A) component of NuRD. The ETO2 nervy homology region 4 (NHR4) domain interacts with multiple polyproline-leucine motifs within GATAD2A. We demonstrate that oligomerization of the ETO2 nervy homology region 3 (NHR3) enhances its affinity for peptides containing at least two polyproline-leucine motifs. Replacing the native motifs from GATAD2A with a higher-affinity sequence from known-binder N-CoR markedly enhances binding affinity, yielding a peptide that disrupts the interaction between ETO2 and target proteins. Enforced peptide expression elevates γ-globin expression levels and induces differentiation of HUDEP-2 and K562 cells. These findings provide insight into ETO2-mediated recruitment of co-regulatory proteins and yield a novel approach for ETO2 inhibition through multivalent binding of the NHR4 domain.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"97 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145491","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