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ProTox 3.0: a webserver for the prediction of toxicity of chemicals Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-22 Priyanka Banerjee, Emanuel Kemmler, Mathias Dunkel, Robert Preissner
Interaction with chemicals, present in drugs, food, environments, and consumer goods, is an integral part of our everyday life. However, depending on the amount and duration, such interactions can also result in adverse effects. With the increase in computational methods, the in silico methods can offer significant benefits to both regulatory needs and requirements for risk assessments and the pharmaceutical
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admetSAR3.0: a comprehensive platform for exploration, prediction and optimization of chemical ADMET properties Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-22 Yaxin Gu, Zhuohang Yu, Yimeng Wang, Long Chen, Chaofeng Lou, Chen Yang, Weihua Li, Guixia Liu, Yun Tang
Absorption, distribution, metabolism, excretion and toxicity (ADMET) properties play a crucial role in drug discovery and chemical safety assessment. Built on the achievements of admetSAR and its successor, admetSAR2.0, this paper introduced the new version of the series, admetSAR3.0, as a comprehensive platform for chemical ADMET assessment, including search, prediction and optimization modules. In
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Extensive long-range polycomb interactions and weak compartmentalization are hallmarks of human neuronal 3D genome Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-22 Ilya A Pletenev, Maria Bazarevich, Diana R Zagirova, Anna D Kononkova, Alexander V Cherkasov, Olga I Efimova, Eugenia A Tiukacheva, Kirill V Morozov, Kirill A Ulianov, Dmitriy Komkov, Anna V Tvorogova, Vera E Golimbet, Nikolay V Kondratyev, Sergey V Razin, Philipp Khaitovich, Sergey V Ulianov, Ekaterina E Khrameeva
Chromatin architecture regulates gene expression and shapes cellular identity, particularly in neuronal cells. Specifically, polycomb group (PcG) proteins enable establishment and maintenance of neuronal cell type by reorganizing chromatin into repressive domains that limit the expression of fate-determining genes and sustain distinct gene expression patterns in neurons. Here, we map the 3D genome
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Massively parallel identification of sequence motifs triggering ribosome-associated mRNA quality control Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-22 Katharine Y Chen, Heungwon Park, Arvind Rasi Subramaniam
Decay of mRNAs can be triggered by ribosome slowdown at stretches of rare codons or positively charged amino acids. However, the full diversity of sequences that trigger co-translational mRNA decay is poorly understood. To comprehensively identify sequence motifs that trigger mRNA decay, we use a massively parallel reporter assay to measure the effect of all possible combinations of codon pairs on
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SifiNet: a robust and accurate method to identify feature gene sets and annotate cells Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-22 Qi Gao, Zhicheng Ji, Liuyang Wang, Kouros Owzar, Qi-Jing Li, Cliburn Chan, Jichun Xie
SifiNet is a robust and accurate computational pipeline for identifying distinct gene sets, extracting and annotating cellular subpopulations, and elucidating intrinsic relationships among these subpopulations. Uniquely, SifiNet bypasses the cell clustering stage, commonly integrated into other cellular annotation pipelines, thereby circumventing potential inaccuracies in clustering that may compromise
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MutationExplorer: a webserver for mutation of proteins and 3D visualization of energetic impacts Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-22 Michelle Philipp, Christopher W Moth, Nikola Ristic, Johanna K S Tiemann, Florian Seufert, Aleksandra Panfilova, Jens Meiler, Peter W Hildebrand, Amelie Stein, Daniel Wiegreffe, René Staritzbichler
The possible effects of mutations on stability and function of a protein can only be understood in the context of protein 3D structure. The MutationExplorer webserver maps sequence changes onto protein structures and allows users to study variation by inputting sequence changes. As the user enters variants, the 3D model evolves, and estimated changes in energy are highlighted. In addition to a basic
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The discovery of novel noncoding RNAs in 50 bacterial genomes Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-22 Aya Narunsky, Gadareth A Higgs, Blake M Torres, Diane Yu, Gabriel Belem de Andrade, Kumari Kavita, Ronald R Breaker
Structured noncoding RNAs (ncRNAs) contribute to many important cellular processes involving chemical catalysis, molecular recognition and gene regulation. Few ncRNA classes are broadly distributed among organisms from all three domains of life, but the list of rarer classes that exhibit surprisingly diverse functions is growing. We previously developed a computational pipeline that enables the near-comprehensive
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Live-cell imaging reveals the trade-off between target search flexibility and efficiency for Cas9 and Cas12a Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-22 Lorenzo Olivi, Cleo Bagchus, Victor Pool, Ezra Bekkering, Konstantin Speckner, Hidde Offerhaus, Wen Y Wu, Martin Depken, Koen J A Martens, Raymond H J Staals, Johannes Hohlbein
CRISPR-Cas systems have widely been adopted as genome editing tools, with two frequently employed Cas nucleases being SpyCas9 and LbCas12a. Although both nucleases use RNA guides to find and cleave target DNA sites, the two enzymes differ in terms of protospacer-adjacent motif (PAM) requirements, guide architecture and cleavage mechanism. In the last years, rational engineering led to the creation
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Comprehensive genomic features indicative for Notch responsiveness Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-22 Benedetto Daniele Giaimo, Tobias Friedrich, Francesca Ferrante, Marek Bartkuhn, Tilman Borggrefe
Transcription factor RBPJ is the central component in Notch signal transduction and directly forms a coactivator complex together with the Notch intracellular domain (NICD). While RBPJ protein levels remain constant in most tissues, dynamic expression of Notch target genes varies depending on the given cell-type and the Notch activity state. To elucidate dynamic RBPJ binding genome-wide, we investigated
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Genome-wide screening and functional validation of methylation barriers near promoters Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-22 Jingmin Shu, Jaroslav Jelinek, Hai Chen, Yan Zhang, Taichun Qin, Ming Li, Li Liu, Jean-Pierre J Issa
CpG islands near promoters are normally unmethylated despite being surrounded by densely methylated regions. Aberrant hypermethylation of these CpG islands has been associated with the development of various human diseases. Although local genetic elements have been speculated to play a role in protecting promoters from methylation, only a limited number of methylation barriers have been identified
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Comprehensive profiling of L1 retrotransposons in mouse Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-22 Xuanming Zhang, Ivana Celic, Hannah Mitchell, Sam Stuckert, Lalitha Vedula, Jeffrey S Han
L1 elements are retrotransposons currently active in mammals. Although L1s are typically silenced in most normal tissues, elevated L1 expression is associated with a variety of conditions, including cancer, aging, infertility and neurological disease. These associations have raised interest in the mapping of human endogenous de novo L1 insertions, and a variety of methods have been developed for this
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High-density generation of spatial transcriptomics with STAGE Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-22 Shang Li, Kuo Gai, Kangning Dong, Yiyang Zhang, Shihua Zhang
Spatial transcriptome technologies have enabled the measurement of gene expression while maintaining spatial location information for deciphering the spatial heterogeneity of biological tissues. However, they were heavily limited by the sparse spatial resolution and low data quality. To this end, we develop a spatial location-supervised auto-encoder generator STAGE for generating high-density spatial
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RNase E searches for cleavage sites in RNA by linear diffusion: direct evidence from single-molecule FRET Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-22 Tithi Banerjee, Eli Rothenberg, Joel G Belasco
The ability of obstacles in cellular transcripts to protect downstream but not upstream sites en masse from attack by RNase E has prompted the hypothesis that this mRNA-degrading endonuclease may scan 5′-monophosphorylated RNA linearly for cleavage sites, starting at the 5′ end. However, despite its proposed regulatory importance, the migration of RNase E on RNA has never been directly observed. We
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The structure assessment web server: for proteins, complexes and more Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-18 Andrew M Waterhouse, Gabriel Studer, Xavier Robin, Stefan Bienert, Gerardo Tauriello, Torsten Schwede
The ‘structure assessment’ web server is a one-stop shop for interactive evaluation and benchmarking of structural models of macromolecular complexes including proteins and nucleic acids. A user-friendly web dashboard links sequence with structure information and results from a variety of state-of-the-art tools, which facilitates the visual exploration and evaluation of structure models. The dashboard
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m6ACali: machine learning-powered calibration for accurate m6A detection in MeRIP-Seq Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-18 Haokai Ye, Tenglong Li, Daniel J Rigden, Zhen Wei
We present m6ACali, a novel machine-learning framework aimed at enhancing the accuracy of N6-methyladenosine (m6A) epitranscriptome profiling by reducing the impact of non-specific antibody enrichment in MeRIP-Seq. The calibration model serves as a genomic feature-based classifier that refines the identification of m6A sites, distinguishing those genuinely present from those that can be detected in
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DetSpace: a web server for engineering detectable pathways for bio-based chemical production Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-18 Hèctor Martín Lázaro, Ricardo Marín Bautista, Pablo Carbonell
Tackling climate change challenges requires replacing current chemical industrial processes through the rational and sustainable use of biodiversity resources. To that end, production routes to key bio-based chemicals for the bioeconomy have been identified. However, their production still remains inefficient in terms of titers, rates, and yields; because of the hurdles found when scaling up. In order
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Deep-PK: deep learning for small molecule pharmacokinetic and toxicity prediction Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-18 Yoochan Myung, Alex G C de Sá, David B Ascher
Evaluating pharmacokinetic properties of small molecules is considered a key feature in most drug development and high-throughput screening processes. Generally, pharmacokinetics, which represent the fate of drugs in the human body, are described from four perspectives: absorption, distribution, metabolism and excretion—all of which are closely related to a fifth perspective, toxicity (ADMET). Since
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Biochemical and structural characterization of Fapy•dG replication by Human DNA polymerase β Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-18 Shijun Gao, Peyton N Oden, Benjamin J Ryan, Haozhe Yang, Bret D Freudenthal, Marc M Greenberg
N6-(2-deoxy-α,β-d-erythro-pentofuranosyl)-2,6-diamino-4-hydroxy-5-formamido-pyrimidine (Fapy•dG) is formed from a common intermediate and in comparable amounts to the well-studied mutagenic DNA lesion 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-OxodGuo). Fapy•dG preferentially gives rise to G → T transversions and G → A transitions. However, the molecular basis by which Fapy•dG is processed by DNA polymerases
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Proximal telomeric decompaction due to telomere shortening drives FOXC1-dependent myocardial senescence Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-18 Bin Li, Weiyao Xiong, Wu Zuo, Yuanyuan Shi, Teng Wang, Lingling Chang, Yueheng Wu, Heng Ma, Qian Bian, Alex C Y Chang
Telomeres, TTAGGGn DNA repeat sequences located at the ends of eukaryotic chromosomes, play a pivotal role in aging and are targets of DNA damage response. Although we and others have demonstrated presence of short telomeres in genetic cardiomyopathic and heart failure cardiomyocytes, little is known about the role of telomere lengths in cardiomyocyte. Here, we demonstrate that in heart failure patient
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Examining chromatin heterogeneity through PacBio long-read sequencing of M.EcoGII methylated genomes: an m6A detection efficiency and calling bias correcting pipeline Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-18 Allison F Dennis, Zhuwei Xu, David J Clark
Recent studies have combined DNA methyltransferase footprinting of genomic DNA in nuclei with long-read sequencing, resulting in detailed chromatin maps for multi-kilobase stretches of genomic DNA from one cell. Theoretically, nucleosome footprints and nucleosome-depleted regions can be identified using M.EcoGII, which methylates adenines in any sequence context, providing a high-resolution map of
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Interplay of the Tfb1 pleckstrin homology domain with Rad2 and Rad4 in transcription coupled and global genomic nucleotide excision repair Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-18 Wenzhi Gong, Hannah Holmberg, Cheng Lu, Michelle Huang, Shisheng Li
Transcription-coupled repair (TCR) and global genomic repair (GGR) are two subpathways of nucleotide excision repair (NER). The TFIIH subunit Tfb1 contains a Pleckstrin homology domain (PHD), which was shown to interact with one PHD-binding segment (PB) of Rad4 and two PHD-binding segments (PB1 and PB2) of Rad2 in vitro. Whether and how the different Rad2 and Rad4 PBs interact with the same Tfb1 PHD
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SARS-CoV-2 nsp15 preferentially degrades AU-rich dsRNA via its dsRNA nickase activity Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-18 Xionglue Wang, Bin Zhu
It has been proposed that coronavirus nsp15 mediates evasion of host cell double-stranded (ds) RNA sensors via its uracil-specific endoribonuclease activity. However, how nsp15 processes viral dsRNA, commonly considered as a genome replication intermediate, remains elusive. Previous research has mainly focused on short single-stranded RNA as substrates, and whether nsp15 prefers single-stranded or
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RNAscape: geometric mapping and customizable visualization of RNA structure Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-17 Raktim Mitra, Ari S Cohen, Remo Rohs
Analyzing and visualizing the tertiary structure and complex interactions of RNA is essential for being able to mechanistically decipher their molecular functions in vivo. Secondary structure visualization software can portray many aspects of RNA; however, these layouts are often unable to preserve topological correspondence since they do not consider tertiary interactions between different regions
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Human AAA+ ATPase FIGNL1 suppresses RAD51-mediated ultra-fine bridge formation Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-10 Kenichiro Matsuzaki, Akira Shinohara, Miki Shinohara
RAD51 filament is crucial for the homology-dependent repair of DNA double-strand breaks and stalled DNA replication fork protection. Positive and negative regulators control RAD51 filament assembly and disassembly. RAD51 is vital for genome integrity but excessive accumulation of RAD51 on chromatin causes genome instability and growth defects. However, the detailed mechanism underlying RAD51 disassembly
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Assembly of SARS-CoV-2 nucleocapsid protein with nucleic acid Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-08 Huaying Zhao, Abdullah M Syed, Mir M Khalid, Ai Nguyen, Alison Ciling, Di Wu, Wai-Ming Yau, Sanjana Srinivasan, Dominic Esposito, Jennifer A Doudna, Grzegorz Piszczek, Melanie Ott, Peter Schuck
The viral genome of SARS-CoV-2 is packaged by the nucleocapsid (N-)protein into ribonucleoprotein particles (RNPs), 38 ± 10 of which are contained in each virion. Their architecture has remained unclear due to the pleomorphism of RNPs, the high flexibility of N-protein intrinsically disordered regions, and highly multivalent interactions between viral RNA and N-protein binding sites in both N-terminal
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Disruption of G-quadruplex dynamicity by BRCA2 abrogation instigates phase separation and break-induced replication at telomeres Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-08 Jennifer J Lee, Hyungmin Kim, Haemin Park, UkJin Lee, Chaelim Kim, Min Lee, Yongdae Shin, Ji-Jung Jung, Han-Byoel Lee, Wonshik Han, Hyunsook Lee
Dynamic interaction between BRCA2 and telomeric G-quadruplexes (G4) is crucial for maintaining telomere replication homeostasis. Cells lacking BRCA2 display telomeric damage with a subset of these cells bypassing senescence to initiate break-induced replication (BIR) for telomere synthesis. Here we show that the abnormal stabilization of telomeric G4 following BRCA2 depletion leads to telomeric repeat-containing
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Identifying human pre-mRNA cleavage and polyadenylation factors by genome-wide CRISPR screens using a dual fluorescence readthrough reporter Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-08 Zuyao Ni, Nujhat Ahmed, Syed Nabeel-Shah, Xinghua Guo, Shuye Pu, Jingwen Song, Edyta Marcon, Giovanni L Burke, Amy Hin Yan Tong, Katherine Chan, Kevin C H Ha, Benjamin J Blencowe, Jason Moffat, Jack F Greenblatt
Messenger RNA precursors (pre-mRNA) generally undergo 3′ end processing by cleavage and polyadenylation (CPA), which is specified by a polyadenylation site (PAS) and adjacent RNA sequences and regulated by a large variety of core and auxiliary CPA factors. To date, most of the human CPA factors have been discovered through biochemical and proteomic studies. However, genetic identification of the human
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Bridging DNA contacts allow Dps from E. coli to condense DNA Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-04 Sneha Shahu, Natalia Vtyurina, Moumita Das, Anne S Meyer, Mahipal Ganji, Elio A Abbondanzieri
The DNA-binding protein from starved cells (Dps) plays a crucial role in maintaining bacterial cell viability during periods of stress. Dps is a nucleoid-associated protein that interacts with DNA to create biomolecular condensates in live bacteria. Purified Dps protein can also rapidly form large complexes when combined with DNA in vitro. However, the mechanism that allows these complexes to nucleate
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PubTator 3.0: an AI-powered literature resource for unlocking biomedical knowledge Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-04 Chih-Hsuan Wei, Alexis Allot, Po-Ting Lai, Robert Leaman, Shubo Tian, Ling Luo, Qiao Jin, Zhizheng Wang, Qingyu Chen, Zhiyong Lu
PubTator 3.0 (https://www.ncbi.nlm.nih.gov/research/pubtator3/) is a biomedical literature resource using state-of-the-art AI techniques to offer semantic and relation searches for key concepts like proteins, genetic variants, diseases and chemicals. It currently provides over one billion entity and relation annotations across approximately 36 million PubMed abstracts and 6 million full-text articles
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Protein G-quadruplex interactions and their effects on phase transitions and protein aggregation Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-04 Bikash R Sahoo, Vojč Kocman, Nathan Clark, Nikhil Myers, Xiexiong Deng, Ee L Wong, Harry J Yang, Anita Kotar, Bryan B Guzman, Daniel Dominguez, Janez Plavec, James C A Bardwell
The SERF family of proteins were originally discovered for their ability to accelerate amyloid formation. Znf706 is an uncharacterized protein whose N-terminus is homologous to SERF proteins. We show here that human Znf706 can promote protein aggregation and amyloid formation. Unexpectedly, Znf706 specifically interacts with stable, non-canonical nucleic acid structures known as G-quadruplexes. G-quadruplexes
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Fine-tuning the tRNA anticodon arm for multiple/consecutive incorporations of β-amino acids and analogs Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-04 Takayuki Katoh, Hiroaki Suga
Ribosomal incorporation of β-amino acids into nascent peptides is much less efficient than that of the canonical α-amino acids. To overcome this, we have engineered a tRNA chimera bearing T-stem of tRNAGlu and D-arm of tRNAPro1, referred to as tRNAPro1E2, which efficiently recruits EF-Tu and EF-P. Using tRNAPro1E2 indeed improved β-amino acid incorporation. However, multiple/consecutive incorporations
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SingmiR: a single-cell miRNA alignment and analysis tool Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-04 Annika Engel, Shusruto Rishik, Pascal Hirsch, Verena Keller, Tobias Fehlmann, Fabian Kern, Andreas Keller
Single-cell RNA sequencing (RNA-seq) has revolutionized our understanding of cell biology, developmental and pathophysiological molecular processes, paving the way toward novel diagnostic and therapeutic approaches. However, most of the gene regulatory processes on the single-cell level are still unknown, including post-transcriptional control conferred by microRNAs (miRNAs). Like the established single-cell
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ADMETlab 3.0: an updated comprehensive online ADMET prediction platform enhanced with broader coverage, improved performance, API functionality and decision support Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-04 Li Fu, Shaohua Shi, Jiacai Yi, Ningning Wang, Yuanhang He, Zhenxing Wu, Jinfu Peng, Youchao Deng, Wenxuan Wang, Chengkun Wu, Aiping Lyu, Xiangxiang Zeng, Wentao Zhao, Tingjun Hou, Dongsheng Cao
ADMETlab 3.0 is the second updated version of the web server that provides a comprehensive and efficient platform for evaluating ADMET-related parameters as well as physicochemical properties and medicinal chemistry characteristics involved in the drug discovery process. This new release addresses the limitations of the previous version and offers broader coverage, improved performance, API functionality
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DEGRONOPEDIA: a web server for proteome-wide inspection of degrons Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-03 Natalia A Szulc, Filip Stefaniak, Małgorzata Piechota, Anna Soszyńska, Gabriela Piórkowska, Andrea Cappannini, Janusz M Bujnicki, Chiara Maniaci, Wojciech Pokrzywa
E3 ubiquitin ligases recognize substrates through their short linear motifs termed degrons. While degron-signaling has been a subject of extensive study, resources for its systematic screening are limited. To bridge this gap, we developed DEGRONOPEDIA, a web server that searches for degrons and maps them to nearby residues that can undergo ubiquitination and disordered regions, which may act as protein
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The effect of pseudoknot base pairing on cotranscriptional structural switching of the fluoride riboswitch Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-03 Laura M Hertz, Elise N White, Konstantin Kuznedelov, Luyi Cheng, Angela M Yu, Rivaan Kakkaramadam, Konstantin Severinov, Alan Chen, Julius B Lucks
A central question in biology is how RNA sequence changes influence dynamic conformational changes during cotranscriptional folding. Here we investigated this question through the study of transcriptional fluoride riboswitches, non-coding RNAs that sense the fluoride anion through the coordinated folding and rearrangement of a pseudoknotted aptamer domain and a downstream intrinsic terminator expression
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H3.1/3.2 regulate the initial progression of the gene expression program Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-03 Satoshi Funaya, Yusuke Takahashi, Masataka G Suzuki, Yutaka Suzuki, Fugaku Aoki
In mice, transcription from the zygotic genome is initiated at the mid-one-cell stage, and occurs promiscuously in many areas of the genome, including intergenic regions. Regulated transcription from selected genes is established during the two-cell stage. This dramatic change in the gene expression pattern marks the initiation of the gene expression program and is essential for early development.
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Mitolnc controls cardiac BCAA metabolism and heart hypertrophy by allosteric activation of BCKDH Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-03 Maria Weiss, Sara Hettrich, Theresa Hofmann, Salma Hachim, Stefan Günther, Thomas Braun, Thomas Boettger
Enzyme activity is determined by various different mechanisms, including posttranslational modifications and allosteric regulation. Allosteric activators are often metabolites but other molecules serve similar functions. So far, examples of long non-coding RNAs (lncRNAs) acting as allosteric activators of enzyme activity are missing. Here, we describe the function of mitolnc in cardiomyocytes, a nuclear
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Resolving the intricate binding of neomycin B to multiple binding motifs of a neomycin-sensing riboswitch aptamer by native top-down mass spectrometry and NMR spectroscopy Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-03 Sarah Viola Heel, Fabian Juen, Karolina Bartosik, Ronald Micura, Christoph Kreutz, Kathrin Breuker
Understanding small molecule binding to RNA can be complicated by an intricate interplay between binding stoichiometry, multiple binding motifs, different occupancies of different binding motifs, and changes in the structure of the RNA under study. Here, we use native top-down mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy to experimentally resolve these factors and gain a
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RecA-dependent or independent recombination of plasmid DNA generates a conflict with the host EcoKI immunity by launching restriction alleviation Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-03 Mikhail Skutel, Daria Yanovskaya, Alina Demkina, Aleksandr Shenfeld, Olga Musharova, Konstantin Severinov, Artem Isaev
Bacterial defence systems are tightly regulated to avoid autoimmunity. In Type I restriction–modification (R–M) systems, a specific mechanism called restriction alleviation (RA) controls the activity of the restriction module. In the case of the Escherichia coli Type I R–M system EcoKI, RA proceeds through ClpXP-mediated proteolysis of restriction complexes bound to non-methylated sites that appear
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BRD2 promotes antibody class switch recombination by facilitating DNA repair in collaboration with NIPBL Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-03 Santosh K Gothwal, Ahmed M Refaat, Mikiyo Nakata, Andre Stanlie, Tasuku Honjo, Nasim A Begum
Efficient repair of DNA double-strand breaks in the Ig heavy chain gene locus is crucial for B-cell antibody class switch recombination (CSR). The regulatory dynamics of the repair pathway direct CSR preferentially through nonhomologous end joining (NHEJ) over alternative end joining (AEJ). Here, we demonstrate that the histone acetyl reader BRD2 suppresses AEJ and aberrant recombination as well as
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Multiplexed in-situ mutagenesis driven by a dCas12a-based dual-function base editor Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-03 Yaokang Wu, Yang Li, Yanfeng Liu, Xiang Xiu, Jiaheng Liu, Linpei Zhang, Jianghua Li, Guocheng Du, Xueqin Lv, Jian Chen, Rodrigo Ledesma-Amaro, Long Liu
Mutagenesis driving genetic diversity is vital for understanding and engineering biological systems. However, the lack of effective methods to generate in-situ mutagenesis in multiple genomic loci combinatorially limits the study of complex biological functions. Here, we design and construct MultiduBE, a dCas12a-based multiplexed dual-function base editor, in an all-in-one plasmid for performing combinatorial
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Unearthing a novel function of SRSF1 in binding and unfolding of RNA G-quadruplexes Nucleic Acids Res. (IF 14.9) Pub Date : 2024-04-03 Naiduwadura Ivon Upekala De Silva, Nathan Lehman, Talia Fargason, Trenton Paul, Zihan Zhang, Jun Zhang
SRSF1 governs splicing of over 1500 mRNA transcripts. SRSF1 contains two RNA-recognition motifs (RRMs) and a C-terminal Arg/Ser-rich region (RS). It has been thought that SRSF1 RRMs exclusively recognize single-stranded exonic splicing enhancers, while RS lacks RNA-binding specificity. With our success in solving the insolubility problem of SRSF1, we can explore the unknown RNA-binding landscape of
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A phage nucleus-associated RNA-binding protein is required for jumbo phage infection Nucleic Acids Res. (IF 14.9) Pub Date : 2024-03-30 Eray Enustun, Emily G Armbruster, Jina Lee, Sitao Zhang, Brian A Yee, Kseniya Malukhina, Yajie Gu, Amar Deep, Jack T Naritomi, Qishan Liang, Stefan Aigner, Benjamin A Adler, Brady F Cress, Jennifer A Doudna, Vorrapon Chaikeeratisak, Don W Cleveland, Majid Ghassemian, Bogdan Bintu, Gene W Yeo, Joe Pogliano, Kevin D Corbett
Large-genome bacteriophages (jumbo phages) of the proposed family Chimalliviridae assemble a nucleus-like compartment bounded by a protein shell that protects the replicating phage genome from host-encoded restriction enzymes and DNA-targeting CRISPR-Cas nucleases. While the nuclear shell provides broad protection against host nucleases, it necessitates transport of mRNA out of the nucleus-like compartment
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Critical steps in the assembly process of the bacterial 50S ribosomal subunit Nucleic Acids Res. (IF 14.9) Pub Date : 2024-03-30 Amal Seffouh, Rainer Nikolay, Joaquin Ortega
During assembly, ribosomal particles in bacteria fold according to energy landscapes comprised of multiple parallel pathways. Cryo-electron microscopy studies have identified a critical maturation step that occurs during the late assembly stages of the 50S subunit in Bacillus subtilis. This step acts as a point of convergency for all the parallel assembly pathways of the subunit, where an assembly
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APLF facilitates interstrand DNA crosslink repair and replication fork protection to confer cisplatin resistance Nucleic Acids Res. (IF 14.9) Pub Date : 2024-03-23 Cheng-Kuei Wu, Jia-Lin Shiu, Chao-Liang Wu, Chi-Feng Hung, Yen-Chih Ho, Yen-Tzu Chen, Sheng-Yung Tung, Cheng-Fa Yeh, Che-Hung Shen, Hungjiun Liaw, Wen-Pin Su
Replication stress converts the stalled forks into reversed forks, which is an important protection mechanism to prevent fork degradation and collapse into poisonous DNA double-strand breaks (DSBs). Paradoxically, the mechanism also acts in cancer cells to contribute to chemoresistance against various DNA-damaging agents. PARP1 binds to and is activated by stalled forks to facilitate fork reversal
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S-phase checkpoint prevents leading strand degradation from strand-associated nicks at stalled replication forks Nucleic Acids Res. (IF 14.9) Pub Date : 2024-03-23 Alberto Bugallo, Mar Sánchez, María Fernández-García, Mónica Segurado
The S-phase checkpoint is involved in coupling DNA unwinding with nascent strand synthesis and is critical to maintain replication fork stability in conditions of replicative stress. However, its role in the specific regulation of leading and lagging strands at stalled forks is unclear. By conditionally depleting RNaseH2 and analyzing polymerase usage genome-wide, we examine the enzymology of DNA replication
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MIWI N-terminal arginines orchestrate generation of functional pachytene piRNAs and spermiogenesis Nucleic Acids Res. (IF 14.9) Pub Date : 2024-03-23 Nicholas Vrettos, Jan Oppelt, Ansgar Zoch, Paraskevi Sgourdou, Haruka Yoshida, Brian Song, Ryan Fink, Dónal O’Carroll, Zissimos Mourelatos
N-terminal arginine (NTR) methylation is a conserved feature of PIWI proteins, which are central components of the PIWI-interacting RNA (piRNA) pathway. The significance and precise function of PIWI NTR methylation in mammals remains unknown. In mice, PIWI NTRs bind Tudor domain containing proteins (TDRDs) that have essential roles in piRNA biogenesis and the formation of the chromatoid body. Using
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The zinc-finger protein Z4 cooperates with condensin II to regulate somatic chromosome pairing and 3D chromatin organization Nucleic Acids Res. (IF 14.9) Pub Date : 2024-03-23 Marta Puerto, Mamta Shukla, Paula Bujosa, Juan Pérez-Roldán, Mònica Torràs-Llort, Srividya Tamirisa, Albert Carbonell, Carme Solé, Joynob Akter Puspo, Christopher T Cummings, Eulàlia de Nadal, Francesc Posas, Fernando Azorín, M Jordan Rowley
Chromosome pairing constitutes an important level of genome organization, yet the mechanisms that regulate pairing in somatic cells and the impact on 3D chromatin organization are still poorly understood. Here, we address these questions in Drosophila, an organism with robust somatic pairing. In Drosophila, pairing preferentially occurs at loci consisting of numerous architectural protein binding sites
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ARGLU1 enhances promoter-proximal pausing of RNA polymerase II and stimulates DNA damage repair Nucleic Acids Res. (IF 14.9) Pub Date : 2024-03-23 Scott Bachus, Nikolas Akkerman, Lauren Fulham, Drayson Graves, Rafe Helwer, Jordan Rempel, Peter Pelka
Arginine and glutamate rich 1 (ARGLU1) is a poorly understood cellular protein with functions in RNA splicing and transcription. Computational prediction suggests that ARGLU1 contains intrinsically disordered regions and lacks any known structural or functional domains. We used adenovirus Early protein 1A (E1A) to probe for critical regulators of important cellular pathways and identified ARGLU1 as
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txtools: an R package facilitating analysis of RNA modifications, structures, and interactions Nucleic Acids Res. (IF 14.9) Pub Date : 2024-03-21 Miguel Angel Garcia-Campos, Schraga Schwartz
We present txtools, an R package that enables the processing, analysis, and visualization of RNA-seq data at the nucleotide-level resolution, seamlessly integrating alignments to the genome with transcriptomic representation. txtools’ main inputs are BAM files and a transcriptome annotation, and the main output is a table, capturing mismatches, deletions, and the number of reads beginning and ending
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Dux activates metabolism-lactylation-MET network during early iPSC reprogramming with Brg1 as the histone lactylation reader Nucleic Acids Res. (IF 14.9) Pub Date : 2024-03-21 Xinglin Hu, Xingwei Huang, Yue Yang, Yuchen Sun, Yanhua Zhao, Zhijing Zhang, Dan Qiu, Yanshuang Wu, Guangming Wu, Lei Lei
The process of induced pluripotent stem cells (iPSCs) reprogramming involves several crucial events, including the mesenchymal-epithelial transition (MET), activation of pluripotent genes, metabolic reprogramming, and epigenetic rewiring. Although these events intricately interact and influence each other, the specific element that regulates the reprogramming network remains unclear. Dux, a factor
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Comprehensive analysis of intramolecular G-quadruplex structures: furthering the understanding of their formalism Nucleic Acids Res. (IF 14.9) Pub Date : 2024-03-21 Marc Farag, Liliane Mouawad
G-quadruplexes (G4) are helical structures found in guanine-rich DNA or RNA sequences. Generally, their formalism is based on a few dozen structures, which can produce some inconsistencies or incompleteness. Using the website ASC-G4, we analyzed the structures of 333 intramolecular G4s, of all types, which allowed us to clarify some key concepts and present new information. To each of the eight distinguishable
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FUS reads histone H3K36me3 to regulate alternative polyadenylation Nucleic Acids Res. (IF 14.9) Pub Date : 2024-03-19 Junqi Jia, Haonan Fan, Xinyi Wan, Yuan Fang, Zhuoning Li, Yin Tang, Yanjun Zhang, Jun Huang, Dong Fang
Complex organisms generate differential gene expression through the same set of DNA sequences in distinct cells. The communication between chromatin and RNA regulates cellular behavior in tissues. However, little is known about how chromatin, especially histone modifications, regulates RNA polyadenylation. In this study, we found that FUS was recruited to chromatin by H3K36me3 at gene bodies. The H3K36me3
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Substrate specificity of Mycobacterium tuberculosis tRNA terminal nucleotidyltransferase toxin MenT3 Nucleic Acids Res. (IF 14.9) Pub Date : 2024-03-15 Jun Liu, Yuka Yashiro, Yuriko Sakaguchi, Tsutomu Suzuki, Kozo Tomita
Mycobacterium tuberculosis transfer RNA (tRNA) terminal nucleotidyltransferase toxin, MenT3, incorporates nucleotides at the 3′-CCA end of tRNAs, blocking their aminoacylation and inhibiting protein synthesis. Here, we show that MenT3 most effectively adds CMPs to the 3′-CCA end of tRNA. The crystal structure of MenT3 in complex with CTP reveals a CTP-specific nucleotide-binding pocket. The 4-NH2 and
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Molecular mechanism of the one-component regulator RccR on bacterial metabolism and virulence Nucleic Acids Res. (IF 14.9) Pub Date : 2024-03-13 Yibo Zhu, Xingyu Mou, Yingjie Song, Qianqian Zhang, Bo Sun, Huanxiang Liu, Hong Tang, Rui Bao
The regulation of carbon metabolism and virulence is critical for the rapid adaptation of pathogenic bacteria to host conditions. In Pseudomonas aeruginosa, RccR is a transcriptional regulator of genes involved in primary carbon metabolism and is associated with bacterial resistance and virulence, although the exact mechanism is unclear. Our study demonstrates that PaRccR is a direct repressor of the
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Catalytic residues of microRNA Argonautes play a modest role in microRNA star strand destabilization in C. elegans Nucleic Acids Res. (IF 14.9) Pub Date : 2024-03-13 Kasuen Kotagama, Acadia L Grimme, Leah Braviner, Bing Yang, Rima M Sakhawala, Guoyun Yu, Lars Kristian Benner, Leemor Joshua-Tor, Katherine McJunkin
Many microRNA (miRNA)-guided Argonaute proteins can cleave RNA (‘slicing’), even though miRNA-mediated target repression is generally cleavage-independent. Here we use Caenorhabditis elegans to examine the role of catalytic residues of miRNA Argonautes in organismal development. In contrast to previous work, mutations in presumed catalytic residues did not interfere with development when introduced
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Comprehensive transcriptome analysis reveals altered mRNA splicing and post-transcriptional changes in the aged mouse brain Nucleic Acids Res. (IF 14.9) Pub Date : 2024-03-13 Nisha Hemandhar Kumar, Verena Kluever, Emanuel Barth, Sebastian Krautwurst, Mattia Furlan, Mattia Pelizzola, Manja Marz, Eugenio F Fornasiero
A comprehensive understanding of molecular changes during brain aging is essential to mitigate cognitive decline and delay neurodegenerative diseases. The interpretation of mRNA alterations during brain aging is influenced by the health and age of the animal cohorts studied. Here, we carefully consider these factors and provide an in-depth investigation of mRNA splicing and dynamics in the aging mouse
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Structural basis of how MGME1 processes DNA 5′ ends to maintain mitochondrial genome integrity Nucleic Acids Res. (IF 14.9) Pub Date : 2024-03-13 Eric Y C Mao, Han-Yi Yen, Chyuan-Chuan Wu
Mitochondrial genome maintenance exonuclease 1 (MGME1) helps to ensure mitochondrial DNA (mtDNA) integrity by serving as an ancillary 5′-exonuclease for DNA polymerase γ. Curiously, MGME1 exhibits unique bidirectionality in vitro, being capable of degrading DNA from either the 5′ or 3′ end. The structural basis of this bidirectionally and, particularly, how it processes DNA from the 5′ end to assist
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CRISPR antiphage defence mediated by the cyclic nucleotide-binding membrane protein Csx23 Nucleic Acids Res. (IF 14.9) Pub Date : 2024-03-13 Sabine Grüschow, Stuart McQuarrie, Katrin Ackermann, Stephen McMahon, Bela E Bode, Tracey M Gloster, Malcolm F White
CRISPR-Cas provides adaptive immunity in prokaryotes. Type III CRISPR systems detect invading RNA and activate the catalytic Cas10 subunit, which generates a range of nucleotide second messengers to signal infection. These molecules bind and activate a diverse range of effector proteins that provide immunity by degrading viral components and/or by disturbing key aspects of cellular metabolism to slow
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DNA fragility at topologically associated domain boundaries is promoted by alternative DNA secondary structure and topoisomerase II activity Nucleic Acids Res. (IF 14.9) Pub Date : 2024-03-07 Heather M Raimer Young, Pei-Chi Hou, Anna R Bartosik, Naomi D Atkin, Lixin Wang, Zhenjia Wang, Aakrosh Ratan, Chongzhi Zang, Yuh-Hwa Wang
CCCTC-binding factor (CTCF) binding sites are hotspots of genome instability. Although many factors have been associated with CTCF binding site fragility, no study has integrated all fragility-related factors to understand the mechanism(s) of how they work together. Using an unbiased, genome-wide approach, we found that DNA double-strand breaks (DSBs) are enriched at strong, but not weak, CTCF binding