Nucleic Acids Research最新文献_第6页

Multifaceted roles of H2B mono-ubiquitylation in D-loop metabolism during homologous recombination repair.

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-02-08 DOI: 10.1093/nar/gkaf081

Shih-Hsun Hung, Yuan Liang, Wolf-Dietrich Heyer

{"title":"Multifaceted roles of H2B mono-ubiquitylation in D-loop metabolism during homologous recombination repair.","authors":"Shih-Hsun Hung, Yuan Liang, Wolf-Dietrich Heyer","doi":"10.1093/nar/gkaf081","DOIUrl":"https://doi.org/10.1093/nar/gkaf081","url":null,"abstract":"Repairing DNA double-strand breaks is crucial for maintaining genome integrity, which occurs primarily through homologous recombination (HR) in Saccharomyces cerevisiae. Nucleosomes, composed of DNA wrapped around a histone octamer, present a natural barrier to end resection to initiate HR, but the impact on the downstream HR steps of homology search, DNA strand invasion, and repair synthesis remain to be determined. Displacement loops (D-loops) play a pivotal role in HR, yet the influence of chromatin dynamics on D-loop metabolism remains unclear. Using the physical D-loop capture and D-loop extension (DLE) assays to track HR intermediates, we employed genetic analysis to reveal that H2B mono-ubiquitylation (H2Bubi) affects multiple steps during HR repair. We infer that H2Bubi modulates chromatin structure, not only promoting histone degradation for nascent D-loop formation but also stabilizing extended D-loops through nucleosome assembly. Furthermore, H2Bubi regulates DNA resection via Rad9 recruitment to suppress a feedback control mechanism that dampens D-loop formation and DLE at hyper-resected ends. Through physical and genetic assays to determine repair outcomes, we demonstrate that H2Bubi plays a crucial role in preventing break-induced replication and thus promoting genomic stability.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 4","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458985","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

Probabilistic and machine-learning methods for predicting local rates of transcription elongation from nascent RNA sequencing data.

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-02-08 DOI: 10.1093/nar/gkaf092

Lingjie Liu, Yixin Zhao, Rebecca Hassett, Shushan Toneyan, Peter K Koo, Adam Siepel

{"title":"Probabilistic and machine-learning methods for predicting local rates of transcription elongation from nascent RNA sequencing data.","authors":"Lingjie Liu, Yixin Zhao, Rebecca Hassett, Shushan Toneyan, Peter K Koo, Adam Siepel","doi":"10.1093/nar/gkaf092","DOIUrl":"https://doi.org/10.1093/nar/gkaf092","url":null,"abstract":"Rates of transcription elongation vary within and across eukaryotic gene bodies. Here, we introduce new methods for predicting elongation rates from nascent RNA sequencing data. First, we devise a probabilistic model that predicts nucleotide-specific elongation rates as a generalized linear function of nearby genomic and epigenomic features. We validate this model with simulations and apply it to public PRO-seq (Precision Run-On Sequencing) and epigenomic data for four cell types, finding that reductions in local elongation rate are associated with cytosine nucleotides, DNA methylation, splice sites, RNA stem-loops, CTCF (CCCTC-binding factor) binding sites, and several histone marks, including H3K36me3 and H4K20me1. By contrast, increases in local elongation rate are associated with thymines, A+T-rich and low-complexity sequences, and H3K79me2 marks. We then introduce a convolutional neural network that improves our local rate predictions. Our analysis is the first to permit genome-wide predictions of relative nucleotide-specific elongation rates.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 4","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143459062","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

R2DT: a comprehensive platform for visualizing RNA secondary structure.

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-02-08 DOI: 10.1093/nar/gkaf032

Holly McCann, Caeden D Meade, Loren Dean Williams, Anton S Petrov, Philip Z Johnson, Anne E Simon, David Hoksza, Eric P Nawrocki, Patricia P Chan, Todd M Lowe, Carlos Eduardo Ribas, Blake A Sweeney, Fábio Madeira, Stephen Anyango, Sri Devan Appasamy, Mandar Deshpande, Mihaly Varadi, Sameer Velankar, Craig L Zirbel, Aleksei Naiden, Fabrice Jossinet, Anton I Petrov

{"title":"R2DT: a comprehensive platform for visualizing RNA secondary structure.","authors":"Holly McCann, Caeden D Meade, Loren Dean Williams, Anton S Petrov, Philip Z Johnson, Anne E Simon, David Hoksza, Eric P Nawrocki, Patricia P Chan, Todd M Lowe, Carlos Eduardo Ribas, Blake A Sweeney, Fábio Madeira, Stephen Anyango, Sri Devan Appasamy, Mandar Deshpande, Mihaly Varadi, Sameer Velankar, Craig L Zirbel, Aleksei Naiden, Fabrice Jossinet, Anton I Petrov","doi":"10.1093/nar/gkaf032","DOIUrl":"10.1093/nar/gkaf032","url":null,"abstract":"RNA secondary (2D) structure visualization is an essential tool for understanding RNA function. R2DT is a software package designed to visualize RNA 2D structures in consistent, recognizable, and reproducible layouts. The latest release, R2DT 2.0, introduces multiple significant features, including the ability to display position-specific information, such as single nucleotide polymorphisms or SHAPE reactivities. It also offers a new template-free mode allowing visualization of RNAs without pre-existing templates, alongside a constrained folding mode and support for animated visualizations. Users can interactively modify R2DT diagrams, either manually or using natural language prompts, to generate new templates or create publication-quality images. Additionally, R2DT features faster performance, an expanded template library, and a growing collection of compatible tools and utilities. Already integrated into multiple biological databases, R2DT has evolved into a comprehensive platform for RNA 2D visualization, accessible at https://r2dt.bio.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 4","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374469","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 phosphorylation signal activates genome-wide transcriptional control by BfmR, the global regulator of Acinetobacter resistance and virulence.

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-02-08 DOI: 10.1093/nar/gkaf063

Nicole Raustad, Yunfei Dai, Akira Iinishi, Arpita Mohapatra, Mark W Soo, Everett Hay, Gabrielle M Hernandez, Edward Geisinger

{"title":"A phosphorylation signal activates genome-wide transcriptional control by BfmR, the global regulator of Acinetobacter resistance and virulence.","authors":"Nicole Raustad, Yunfei Dai, Akira Iinishi, Arpita Mohapatra, Mark W Soo, Everett Hay, Gabrielle M Hernandez, Edward Geisinger","doi":"10.1093/nar/gkaf063","DOIUrl":"10.1093/nar/gkaf063","url":null,"abstract":"The nosocomial pathogen Acinetobacter baumannii is a major threat to human health. The sensor kinase-response regulator system, BfmS-BfmR, is essential to multidrug resistance and virulence in the bacterium and represents a potential antimicrobial target. Important questions remain about how the system controls resistance and pathogenesis. Although BfmR knockout alters expression of >1000 genes, its direct regulon is undefined. Moreover, how phosphorylation controls the regulator is unclear. Here, we address these problems by combining mutagenesis, ChIP-seq, and in vitro phosphorylation to study the functions of phospho-BfmR. We show that phosphorylation is required for BfmR-mediated gene regulation, antibiotic resistance, and sepsis development in vivo. Consistent with activating the protein, phosphorylation induces dimerization and target DNA affinity. Integrated analysis of genome-wide binding and transcriptional profiles of BfmR led to additional key findings: (1) Phosphorylation dramatically expands the number of genomic sites BfmR binds; (2) DNA recognition involves a direct repeat motif widespread across promoters; (3) BfmR directly regulates 303 genes as activator (e.g., capsule, peptidoglycan, and outer membrane biogenesis) or repressor (pilus biogenesis); (4) BfmR controls several non-coding sRNAs. These studies reveal the centrality of a phosphorylation signal in driving A. baumannii disease and disentangle the extensive pathogenic gene-regulatory network under its control.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 4","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806355/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374494","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

Biomolecular condensation of human IDRs initiates endogenous transcription via intrachromosomal looping or high-density promoter localization.

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-02-08 DOI: 10.1093/nar/gkaf056

Jing Li, Shizhe Liu, Sunghwan Kim, Jacob Goell, Zachary Allen Drum, John Patrick Flores, Alex J Ma, Barun Mahata, Mario Escobar, Alex Raterink, Jeong Hyun Ahn, Erik R Terán, Rosa Selenia Guerra-Resendez, Yuhao Zhou, Bo Yu, Michael R Diehl, Gang Greg Wang, Anna-Karin Gustavsson, Douglas H Phanstiel, Isaac B Hilton

{"title":"Biomolecular condensation of human IDRs initiates endogenous transcription via intrachromosomal looping or high-density promoter localization.","authors":"Jing Li, Shizhe Liu, Sunghwan Kim, Jacob Goell, Zachary Allen Drum, John Patrick Flores, Alex J Ma, Barun Mahata, Mario Escobar, Alex Raterink, Jeong Hyun Ahn, Erik R Terán, Rosa Selenia Guerra-Resendez, Yuhao Zhou, Bo Yu, Michael R Diehl, Gang Greg Wang, Anna-Karin Gustavsson, Douglas H Phanstiel, Isaac B Hilton","doi":"10.1093/nar/gkaf056","DOIUrl":"https://doi.org/10.1093/nar/gkaf056","url":null,"abstract":"Protein intrinsically disordered regions (IDRs) are critical gene-regulatory components and aberrant fusions between IDRs and DNA-binding/chromatin-associating domains cause diverse human cancers. Despite this importance, how IDRs influence gene expression, and how aberrant IDR fusion proteins provoke oncogenesis, remains incompletely understood. Here we develop a series of synthetic dCas9-IDR fusions to establish that locus-specific recruitment of IDRs can be sufficient to stimulate endogenous gene expression. Using dCas9 fused to the paradigmatic leukemogenic NUP98 IDR, we also demonstrate that IDRs can activate transcription via localized biomolecular condensation and in a manner that is dependent upon overall IDR concentration, local binding density, and amino acid composition. To better clarify the oncogenic role of IDRs, we construct clinically observed NUP98 IDR fusions and show that, while generally non-overlapping, oncogenic NUP98-IDR fusions convergently drive a core leukemogenic gene expression program in donor-derived human hematopoietic stem cells. Interestingly, we find that this leukemic program arises through differing mechanistic routes based upon IDR fusion partner; either distributed intragenic binding and intrachromosomal looping, or dense binding at promoters. Altogether, our studies clarify the gene-regulatory roles of IDRs and, for the NUP98 IDR, connect this capacity to pathological cellular programs, creating potential opportunities for generalized and mechanistically tailored therapies.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 4","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143458861","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 'A modular toolbox for the optogenetic deactivation of transcription'.

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-02-08 DOI: 10.1093/nar/gkaf100

引用次数: 0

Ubiquitin protease Ubp1 cooperates with Ubp10 and Ubp12 to revert lysine-164 PCNA ubiquitylation at replication forks.

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-02-08 DOI: 10.1093/nar/gkaf076

Javier Zamarreño, Sergio Rodríguez, Sofía Muñoz, Avelino Bueno, María P Sacristán

{"title":"Ubiquitin protease Ubp1 cooperates with Ubp10 and Ubp12 to revert lysine-164 PCNA ubiquitylation at replication forks.","authors":"Javier Zamarreño, Sergio Rodríguez, Sofía Muñoz, Avelino Bueno, María P Sacristán","doi":"10.1093/nar/gkaf076","DOIUrl":"https://doi.org/10.1093/nar/gkaf076","url":null,"abstract":"Proliferating cell nuclear antigen (PCNA) is essential for the faithful duplication of eukaryotic genomes. PCNA also orchestrates events necessary to address threats to genomic integrity, such as the DNA damage tolerance (DDT) response, a mechanism by which eukaryotic cells bypass replication-blocking lesions to maintain replisome stability. DDT is regulated by the ubiquitylation of PCNA and the consequent recruitment of specialized polymerases that ensure replication continuity. We have recently described that the deubiquitylases Ubp10 and Ubp12 modulate DDT events by reverting the ubiquitylation of PCNA in Saccharomyces cerevisiae. This study identifies Ubp1 as a novel PCNA deubiquitylase that cooperates with Ubp10 and Ubp12 in the regulation of DDT during DNA replication. Ubp1, previously known as a cytoplasmic protein, also localizes to the nucleus, where it associates with DNA replication forks. Additionally, Ubp1 interacts with and deubiquitylates PCNA. Here, we provide evidence that Ubp1 collaborates with Ubp10 and Ubp12 to facilitate DNA replication by efficiently reverting PCNAK164 ubiquitylation at replication forks under conditions free from exogenous perturbations. Consequently, the deletion of UBP1, UBP10, and UBP12 leads to persistent ubiquitylation of PCNAK164 and a marked delay in S phase progression.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 4","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143459133","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 G-quadruplex experimental drug QN-302 impairs liposarcoma cell growth by inhibiting MDM2 expression and restoring p53 levels.

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-02-08 DOI: 10.1093/nar/gkaf085

Beatrice Tosoni, Eisa Naghshineh, Irene Zanin, Irene Gallina, Lorenzo Di Pietro, Loredana Cleris, Matteo Nadai, Mara Lecchi, Paolo Verderio, Pietro Pratesi, Sandro Pasquali, Nadia Zaffaroni, Stephen Neidle, Marco Folini, Sara N Richter

{"title":"The G-quadruplex experimental drug QN-302 impairs liposarcoma cell growth by inhibiting MDM2 expression and restoring p53 levels.","authors":"Beatrice Tosoni, Eisa Naghshineh, Irene Zanin, Irene Gallina, Lorenzo Di Pietro, Loredana Cleris, Matteo Nadai, Mara Lecchi, Paolo Verderio, Pietro Pratesi, Sandro Pasquali, Nadia Zaffaroni, Stephen Neidle, Marco Folini, Sara N Richter","doi":"10.1093/nar/gkaf085","DOIUrl":"10.1093/nar/gkaf085","url":null,"abstract":"Well-differentiated/dedifferentiated liposarcomas (WD/DDLPSs) account for ∼60% of all liposarcomas. They have a poor prognosis due to limited therapeutic options. WD/DDLPSs are characterized by aberrant expression of mouse double minute 2 (MDM2), which forms G-quadruplexes (G4s) in its promoter. Here, we investigated the possibility of targeting WD/DDLPSs with small molecules against the MDM2 G4s. Among the molecules tested, the naphthalene diimide derivative QN-302 significantly impaired WD/DDLPS cell growth and its activity strikingly paralleled cell-specific G4 abundance as measured by CUT&Tag and RNA sequencing analysis. QN-302 stabilized MDM2 G4s at the P2 inducible promoter and prevented polymerase progression from the constitutive P1 promoter, thereby inhibiting the formation of full-length MDM2 transcripts. This resulted in the accumulation of p53 through the p53-MDM2 autoregulatory feedback loop, ultimately leading to apoptotic cell death. In patient-derived xenograft mouse models, QN-302 treatment reduced tumour volume distribution and was well tolerated. We have identified a novel and effective therapeutic strategy to reduce MDM2 expression and promote p53 reactivation in tumours harbouring wild-type TP53, such as WD/DDLPSs.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 4","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11822379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143409502","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 human genome encodes a multitude of novel miRNAs.

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-02-08 DOI: 10.1093/nar/gkaf070

Fan Gao, Fang Wang, Yue Chen, Bolin Deng, Fujian Yang, Huifen Cao, Junjie Chen, Huiling Chen, Fei Qi, Philipp Kapranov

{"title":"The human genome encodes a multitude of novel miRNAs.","authors":"Fan Gao, Fang Wang, Yue Chen, Bolin Deng, Fujian Yang, Huifen Cao, Junjie Chen, Huiling Chen, Fei Qi, Philipp Kapranov","doi":"10.1093/nar/gkaf070","DOIUrl":"10.1093/nar/gkaf070","url":null,"abstract":"Human cells generate a vast complexity of noncoding RNAs, the \"RNA dark matter,\" which includes a vast small RNA (sRNA) transcriptome. The biogenesis, biological relevance, and mechanisms of action of most of these transcripts remain unknown, and they are widely assumed to represent degradation products. Here, we aimed to functionally characterize human sRNA transcriptome by attempting to answer the following question-can a significant number of novel sRNAs correspond to novel members of known classes, specifically, microRNAs (miRNAs)? By developing and validating a miRNA discovery pipeline, we show that at least 2726 novel canonical miRNAs, majority of which represent novel miRNA families, exist in just one human cell line compared to just 1914 known miRNA loci. Moreover, potentially tens of thousands of miRNAs remain to be discovered. Strikingly, many novel miRNAs map to exons of protein-coding genes emphasizing a complex and interleaved architecture of the genome. The existence of so many novel members of a functional class of sRNAs suggest that the human sRNA transcriptome harbors a multitude of novel regulatory molecules. Overall, these results suggest that we are at the very beginning of understanding the true functional complexity of the sRNA component of the \"RNA dark matter.\"","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"53 4","pages":""},"PeriodicalIF":16.6,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11833695/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441156","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

Correction to 'Recruitment of homodimeric proneural factors by conserved CAT-CAT E-boxes drives major epigenetic reconfiguration in cortical neurogenesis'.

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2025-02-08 DOI: 10.1093/nar/gkaf129

引用次数: 0