Nucleic Acids Research最新文献_第8页

STK39-mediated amplification of γ-H2A.X promotes homologous recombination and contributes to PARP inhibitor resistance. STK39介导的γ-H2A.X扩增可促进同源重组并导致PARP抑制剂抗性。

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2024-12-11 DOI: 10.1093/nar/gkae1099

Yi Xu, Changying Li, Huan Yin, Somaira Nowsheen, Xin Xu, Wenjuan Kang, Xin Liu, Lifeng Chen, Zhenkun Lou, Junlin Yi, Min Deng

{"title":"STK39-mediated amplification of γ-H2A.X promotes homologous recombination and contributes to PARP inhibitor resistance.","authors":"Yi Xu, Changying Li, Huan Yin, Somaira Nowsheen, Xin Xu, Wenjuan Kang, Xin Liu, Lifeng Chen, Zhenkun Lou, Junlin Yi, Min Deng","doi":"10.1093/nar/gkae1099","DOIUrl":"10.1093/nar/gkae1099","url":null,"abstract":"The phosphorylation of histone H2A.X into γH2A.X is a crucial early event in the DNA damage response, marking DNA damage sites and initiating repair processes. While ATM kinase is traditionally recognized as the primary mediator of H2A.X phosphorylation, our study identifies serine/threonine kinase 39 (STK39) as a novel enhancer of this critical signaling pathway. We demonstrate that after DNA damage, STK39 undergoes phosphorylation by the ATM kinase, facilitating its interaction with the Mre11-Rad50-Nbs1 complex and subsequent recruitment to chromatin. This recruitment enables STK39 to further phosphorylate H2A.X, thus amplifying γH2A.X production and promoting homologous recombination repair. Notably, we observe a significant upregulation of STK39 in pancreatic adenocarcinoma (PAAD) tissues, correlating with heightened resistance to PARPi therapy. Furthermore, we demonstrate the synergistic efficacy of combining STK39 inhibition with PARP inhibitors in suppressing and reversing PAAD growth. This study not only provides new insights into the molecular dynamics of H2A.X phosphorylation but also highlights the therapeutic potential of targeting STK39 to enhance PARPi sensitivity in PAAD (created with BioRender).","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":" ","pages":"13881-13895"},"PeriodicalIF":16.6,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716710","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

Predicting gene expression from histone marks using chromatin deep learning models depends on histone mark function, regulatory distance and cellular states.

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2024-12-11 DOI: 10.1093/nar/gkae1212

Alan E Murphy, Aydan Askarova, Boris Lenhard, Nathan G Skene, Sarah J Marzi

{"title":"Predicting gene expression from histone marks using chromatin deep learning models depends on histone mark function, regulatory distance and cellular states.","authors":"Alan E Murphy, Aydan Askarova, Boris Lenhard, Nathan G Skene, Sarah J Marzi","doi":"10.1093/nar/gkae1212","DOIUrl":"https://doi.org/10.1093/nar/gkae1212","url":null,"abstract":"To understand the complex relationship between histone mark activity and gene expression, recent advances have used in silico predictions based on large-scale machine learning models. However, these approaches have omitted key contributing factors like cell state, histone mark function or distal effects, which impact the relationship, limiting their findings. Moreover, downstream use of these models for new biological insight is lacking. Here, we present the most comprehensive study of this relationship to date - investigating seven histone marks in eleven cell types across a diverse range of cell states. We used convolutional and attention-based models to predict transcription from histone mark activity at promoters and distal regulatory elements. Our work shows that histone mark function, genomic distance and cellular states collectively influence a histone mark's relationship with transcription. We found that no individual histone mark is consistently the strongest predictor of gene expression across all genomic and cellular contexts. This highlights the need to consider all three factors when determining the effect of histone mark activity on transcriptional state. Furthermore, we conducted in silico histone mark perturbation assays, uncovering functional and disease related loci and highlighting frameworks for the use of chromatin deep learning models to uncover new biological insight.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":" ","pages":""},"PeriodicalIF":16.6,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807293","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

Precision genome editing using combinatorial viral vector delivery of CRISPR-Cas9 nucleases and donor DNA constructs

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2024-12-11 DOI: 10.1093/nar/gkae1213

Zhen Li, Xiaoling Wang, Josephine M Janssen, Jin Liu, Francesca Tasca, Rob C Hoeben, Manuel A F V Gonçalves

{"title":"Precision genome editing using combinatorial viral vector delivery of CRISPR-Cas9 nucleases and donor DNA constructs","authors":"Zhen Li, Xiaoling Wang, Josephine M Janssen, Jin Liu, Francesca Tasca, Rob C Hoeben, Manuel A F V Gonçalves","doi":"10.1093/nar/gkae1213","DOIUrl":"https://doi.org/10.1093/nar/gkae1213","url":null,"abstract":"Genome editing based on programmable nucleases and donor DNA constructs permits introducing specific base-pair changes and complete transgenes or live-cell reporter tags at predefined chromosomal positions. A crucial requirement for such versatile genome editing approaches is, however, the need to co-deliver in an effective, coordinated and non-cytotoxic manner all the required components into target cells. Here, adenoviral (AdV) and adeno-associated viral (AAV) vectors are investigated as delivery agents for, respectively, engineered CRISPR-Cas9 nucleases and donor DNA constructs prone to homologous recombination (HR) or homology-mediated end joining (HMEJ) processes. Specifically, canonical single-stranded and self-complementary double-stranded AAVs served as sources of ectopic HR and HMEJ substrates, whilst second- and third-generation AdVs provided for matched CRISPR-Cas9 nucleases. We report that combining single-stranded AAV delivery of HR donors with third-generation AdV transfer of CRISPR-Cas9 nucleases results in selection-free and precise whole transgene insertion in large fractions of target-cell populations (i.e. up to 93%) and disclose that programmable nuclease-induced chromosomal breaks promote AAV transduction. Finally, besides investigating relationships between distinct AAV structures and genome-editing performance endpoints, we further report that high-fidelity CRISPR-Cas9 nucleases are critical for mitigating off-target chromosomal insertion of defective AAV genomes known to be packaged in vector particles.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"117 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805501","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

Molecular basis for thiocarboxylation and release of Urm1 by its E1-activating enzyme Uba4. Urm1 通过其 E1 激活酶 Uba4 进行硫代羧化和释放的分子基础。

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2024-12-11 DOI: 10.1093/nar/gkae1111

Mikołaj Sokołowski, Dominika Kwasna, Keerthiraju E Ravichandran, Cristian Eggers, Rościsław Krutyhołowa, Magdalena Kaczmarczyk, Bozena Skupien-Rabian, Marcin Jaciuk, Marta Walczak, Priyanka Dahate, Marta Pabis, Małgorzata Jemioła-Rzemińska, Urszula Jankowska, Sebastian A Leidel, Sebastian Glatt

{"title":"Molecular basis for thiocarboxylation and release of Urm1 by its E1-activating enzyme Uba4.","authors":"Mikołaj Sokołowski, Dominika Kwasna, Keerthiraju E Ravichandran, Cristian Eggers, Rościsław Krutyhołowa, Magdalena Kaczmarczyk, Bozena Skupien-Rabian, Marcin Jaciuk, Marta Walczak, Priyanka Dahate, Marta Pabis, Małgorzata Jemioła-Rzemińska, Urszula Jankowska, Sebastian A Leidel, Sebastian Glatt","doi":"10.1093/nar/gkae1111","DOIUrl":"10.1093/nar/gkae1111","url":null,"abstract":"Ubiquitin-related modifier 1 (Urm1) is a highly conserved member of the ubiquitin-like (UBL) family of proteins. Urm1 is a key component of the eukaryotic transfer RNA (tRNA) thiolation cascade, responsible for introducing sulfur at wobble uridine (U34) in several eukaryotic tRNAs. Urm1 must be thiocarboxylated (Urm1-SH) by its E1 activating enzyme UBL protein activator 4 (Uba4). Uba4 first adenylates and then thiocarboxylates the C-terminus of Urm1 using its adenyl-transferase (AD) and rhodanese (RHD) domains. However, the detailed mechanisms of Uba4, the interplay between the two domains, and the release of Urm1 remain elusive. Here, we report a cryo-EM-based structural model of the Uba4/Urm1 complex that reveals the position of its RHD domains after Urm1 binding, and by analyzing the in vitro and in vivo consequence of mutations at the interface, we show its importance for the thiocarboxylation of Urm1. Our results confirm that the formation of the Uba4-Urm1 thioester and thiocarboxylation of Urm1's C-terminus depend on conserved cysteine residues of Uba4 and that the complex avoids unwanted side-reactions of the adenylate by forming a thioester intermediate. We show how the Urm1-SH product can be released and how Urm1 interacts with upstream (Tum1) and downstream (Ncs6) components of the pathway. Our work provides a detailed mechanistic description of the reaction steps that are needed to produce Urm1-SH, which is required to thiolate tRNAs and persulfidate proteins.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":" ","pages":"13980-13995"},"PeriodicalIF":16.6,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823496","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

Chromatin and transcription in Nucleic Acids Research: the first 50 years. 核酸研究中的染色质和转录：第一个 50 年。

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2024-12-11 DOI: 10.1093/nar/gkae1151

Pierre-Antoine Defossez

引用次数: 0

Imaging of endogenous RNA in live cells using sequence-activated fluorescent RNA probes

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2024-12-11 DOI: 10.1093/nar/gkae1209

Haifeng Zheng, Xiyu Liu, Luhui Liu, Jiarui Hu, Xianjun Chen

{"title":"Imaging of endogenous RNA in live cells using sequence-activated fluorescent RNA probes","authors":"Haifeng Zheng, Xiyu Liu, Luhui Liu, Jiarui Hu, Xianjun Chen","doi":"10.1093/nar/gkae1209","DOIUrl":"https://doi.org/10.1093/nar/gkae1209","url":null,"abstract":"RNA performs a remarkable range of functions, such as RNA processing, chromosome maintenance and dosage compensation. Technologies that robustly and specifically image RNA in its native state are highly desirable, as these technologies can help researchers clarify the localization and functionality of diverse RNAs. Here, we describe the development of a sequence-activated fluorescent RNA (SaFR) technique. In SaFR, in the absence of target RNA, the structure of fluorogenic RNA is disrupted by the invader sequence, and the ability to activate the Pepper’s cognate fluorophores is lost as a result. In the presence of target RNA, SaFR undergoes conformational reorganization and transforms into the fluorogenic conformation of Pepper, enabling the activation of fluorophores to produce fluorescent signals. SaFR exhibits favourable properties, such as large dynamic ranges, high specificity and fast fluorescence generation. Further studies showed that exogenous or endogenous RNAs can be tracked in live and fixed cells through SaFR. We further demonstrated the usefulness of SaFR in monitoring the assembly and disassembly of stress granules in real-time. Overall, this study offers a robust and versatile tool for labelling and imaging endogenous RNA in cells, which will be useful for clarifying the functionality and molecular mechanism of RNA.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"49 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805496","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

Exploring the diversity of anti-defense systems across prokaryotes, phages and mobile genetic elements

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2024-12-11 DOI: 10.1093/nar/gkae1171

Florian Tesson, Erin Huiting, Linlin Wei, Jie Ren, Matthew Johnson, Rémi Planel, Jean Cury, Yue Feng, Joseph Bondy-Denomy, Aude Bernheim

{"title":"Exploring the diversity of anti-defense systems across prokaryotes, phages and mobile genetic elements","authors":"Florian Tesson, Erin Huiting, Linlin Wei, Jie Ren, Matthew Johnson, Rémi Planel, Jean Cury, Yue Feng, Joseph Bondy-Denomy, Aude Bernheim","doi":"10.1093/nar/gkae1171","DOIUrl":"https://doi.org/10.1093/nar/gkae1171","url":null,"abstract":"The co-evolution of prokaryotes, phages and mobile genetic elements (MGEs) has driven the diversification of defense and anti-defense systems alike. Anti-defense proteins have diverse functional domains, sequences and are typically small, creating a challenge to detect anti-defense homologs across prokaryotic and phage genomes. To date, no tools comprehensively annotate anti-defense proteins within a desired sequence. Here, we developed ‘AntiDefenseFinder’—a free open-source tool and web service that detects 156 anti-defense systems of one or more proteins in any genomic sequence. Using this dataset, we identified 47 981 anti-defense systems distributed across prokaryotes and their viruses. We found that some genes co-localize in ‘anti-defense islands’, including Escherichia coli T4 and Lambda phages, although many appear standalone. Eighty-nine per cent anti-defense systems localize only or preferentially in MGE. However, &gt;80% of anti-Pycsar protein 1 (Apyc1) resides in nonmobile regions of bacterial genomes. Evolutionary analysis and biochemical experiments revealed that Apyc1 likely originated in bacteria to regulate cyclic nucleotide (cNMP) signaling, but phage co-opted Apyc1 to overcome cNMP-utilizing defenses. With the AntiDefenseFinder tool, we hope to facilitate the identification of the full repertoire of anti-defense systems in MGEs, the discovery of new protein functions and a deeper understanding of host–pathogen arms race.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"82 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805504","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

Novel BRCA1–PLK1–CIP2A axis orchestrates homologous recombination-mediated DNA repair to maintain chromosome integrity during oocyte meiosis

IF 14.9 2区生物学

Nucleic Acids Research Pub Date : 2024-12-11 DOI: 10.1093/nar/gkae1207

Crystal Lee, Jeong Su Oh

{"title":"Novel BRCA1–PLK1–CIP2A axis orchestrates homologous recombination-mediated DNA repair to maintain chromosome integrity during oocyte meiosis","authors":"Crystal Lee, Jeong Su Oh","doi":"10.1093/nar/gkae1207","DOIUrl":"https://doi.org/10.1093/nar/gkae1207","url":null,"abstract":"Double-strand breaks (DSBs) are a formidable threat to genome integrity, potentially leading to cancer and various genetic diseases. The prolonged lifespan of mammalian oocytes increases their susceptibility to DNA damage over time. While somatic cells suppress DSB repair during mitosis, oocytes exhibit a remarkable capacity to repair DSBs during meiotic maturation. However, the precise mechanisms underlying DSB repair in oocytes remain poorly understood. Here, we describe the pivotal role of the BRCA1–PLK1–CIP2A axis in safeguarding genomic integrity during meiotic maturation in oocytes. We found that inhibition of homologous recombination (HR) severely impaired chromosome integrity by generating chromosome fragments during meiotic maturation. Notably, HR inhibition impaired the recruitment of CIP2A to damaged chromosomes, and the depletion of CIP2A led to chromosome fragmentation following DSB induction. Moreover, BRCA1 depletion impaired chromosomal recruitment of CIP2A, but not vice versa. Importantly, the impaired chromosomal recruitment of CIP2A could be rescued by PLK1 inhibition. Consequently, our findings not only underscore the importance of the chromosomal recruitment of CIP2A in preventing chromosome fragmentation, but also demonstrate the regulatory role of the BRCA1–PLK1–CIP2A axis in this process during oocyte meiotic maturation.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":"119 1","pages":""},"PeriodicalIF":14.9,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805505","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

Optimization of ACE-tRNAs function in translation for suppression of nonsense mutations. 优化 ACE-tRNA 在翻译中的功能，以抑制无义突变。

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2024-12-11 DOI: 10.1093/nar/gkae1112

Joseph J Porter, Wooree Ko, Emily G Sorensen, John D Lueck

引用次数: 0

Phosphorylation-mediated disassembly of C-terminal binding protein 2 tetramer impedes epigenetic silencing of pluripotency in mouse embryonic stem cells. 磷酸化介导的 C 端结合蛋白 2 四聚体解体阻碍了小鼠胚胎干细胞多能性的表观遗传沉默。

IF 16.6 2区生物学

Nucleic Acids Research Pub Date : 2024-12-11 DOI: 10.1093/nar/gkae1076

Han-Teo Lee, Young Ah Kim, Sangho Lee, Ye-Eun Jung, Hanbyeol Kim, Tae Wan Kim, Sojung Kwak, Jaehyeon Kim, Chul-Hwan Lee, Sun-Shin Cha, Jinmi Choi, Eun-Jung Cho, Hong-Duk Youn

{"title":"Phosphorylation-mediated disassembly of C-terminal binding protein 2 tetramer impedes epigenetic silencing of pluripotency in mouse embryonic stem cells.","authors":"Han-Teo Lee, Young Ah Kim, Sangho Lee, Ye-Eun Jung, Hanbyeol Kim, Tae Wan Kim, Sojung Kwak, Jaehyeon Kim, Chul-Hwan Lee, Sun-Shin Cha, Jinmi Choi, Eun-Jung Cho, Hong-Duk Youn","doi":"10.1093/nar/gkae1076","DOIUrl":"10.1093/nar/gkae1076","url":null,"abstract":"Cells need to overcome both intrinsic and extrinsic threats. Although pluripotency is associated with damage responses, how stem cells respond to DNA damage remains controversial. Here, we elucidate that DNA damage activates Chk2, leading to the phosphorylation of serine 164 on C-terminal binding protein 2 (Ctbp2). The phosphorylation of Ctbp2 induces the disruption of Ctbp2 tetramer, weakening interactions with zinc finger proteins, leading to the dissociation of phosphorylated Ctbp2 from chromatin. This transition to a monomeric state results in the separation of histone deacetylase 1 from Ctbp2, consequently slowing the rate of H3K27 deacetylation. In contrast to the nucleosome remodeling and deacetylase complex, phosphorylated Ctbp2 increased binding affinity to polycomb repressive complex (PRC)2, interacting through the N-terminal domain of Suz12. Through this domain, Ctbp2 competes with Jarid2, inhibiting the function of PRC2. Thus, the phosphorylation of Ctbp2 under stress conditions represents a precise mechanism aimed at preserving stemness traits by inhibiting permanent transcriptional shutdown.","PeriodicalId":19471,"journal":{"name":"Nucleic Acids Research","volume":" ","pages":"13706-13722"},"PeriodicalIF":16.6,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716702","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