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Taxonomy of introns and the evolution of minor introns Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-29 Anouk M Olthof, Charles F Schwoerer, Kaitlin N Girardini, Audrey L Weber, Karen Doggett, Stephen Mieruszynski, Joan K Heath, Timothy E Moore, Jakob Biran, Rahul N Kanadia
Classification of introns, which is crucial to understanding their evolution and splicing, has historically been binary and has resulted in the naming of major and minor introns that are spliced by their namesake spliceosome. However, a broad range of intron consensus sequences exist, leading us to here reclassify introns as minor, minor-like, hybrid, major-like, major and non-canonical introns in
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Logical regulation of endogenous gene expression using programmable, multi-input processing CRISPR guide RNAs Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-29 Hansol Kang, Dongwon Park, Jongmin Kim
The CRISPR-Cas system provides a versatile RNA-guided approach for a broad range of applications. Thanks to advances in RNA synthetic biology, the engineering of guide RNAs (gRNAs) has enabled the conditional control of the CRISPR-Cas system. However, achieving precise regulation of the CRISPR-Cas system for efficient modulation of internal metabolic processes remains challenging. In this work, we
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Assessing the impact of transcriptomics data analysis pipelines on downstream functional enrichment results Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-29 Victor Paton, Ricardo Omar Ramirez Flores, Attila Gabor, Pau Badia-i-Mompel, Jovan Tanevski, Martin Garrido-Rodriguez, Julio Saez-Rodriguez
Transcriptomics is widely used to assess the state of biological systems. There are many tools for the different steps, such as normalization, differential expression, and enrichment. While numerous studies have examined the impact of method choices on differential expression results, little attention has been paid to their effects on further downstream functional analysis, which typically provides
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PRPF40A induces inclusion of exons in GC-rich regions important for human myeloid cell differentiation Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-29 Cheryl Weiqi Tan, Donald Yuhui Sim, Yashu Zhen, Haobo Tian, Jace Koh, Xavier Roca
We characterized the regulatory mechanisms and role in human myeloid cell survival and differentiation of PRPF40A, a splicing factor lacking a canonical RNA Binding Domain. Upon PRPF40A knockdown, HL-60 cells displayed increased cell death, decreased proliferation and slight differentiation phenotype with upregulation of immune activation genes. Suggestive of both redundant and specific functions,
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TMPyP binding evokes a complex, tunable nanomechanical response in DNA Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-29 Balázs Kretzer, Levente Herényi, Gabriella Csík, Eszter Supala, Ádám Orosz, Hedvig Tordai, Bálint Kiss, Miklós Kellermayer
TMPyP is a porphyrin capable of DNA binding and used in photodynamic therapy and G-quadruplex stabilization. Despite its broad applications, TMPyP’s effect on DNA nanomechanics is unknown. Here we investigated, by manipulating λ-phage DNA with optical tweezers combined with microfluidics in equilibrium and perturbation kinetic experiments, how TMPyP influences DNA nanomechanics across wide ranges of
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Phosphorylation of the nuclear poly(A) binding protein (PABPN1) during mitosis protects mRNA from hyperadenylation and maintains transcriptome dynamics Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-29 Jackson M Gordon, David V Phizicky, Leonard Schärfen, Courtney L Brown, Dahyana Arias Escayola, Jean Kanyo, TuKiet T Lam, Matthew D Simon, Karla M Neugebauer
Polyadenylation controls mRNA biogenesis, nucleo-cytoplasmic export, translation and decay. These processes are interdependent and coordinately regulated by poly(A)-binding proteins (PABPs), yet how PABPs are themselves regulated is not fully understood. Here, we report the discovery that human nuclear PABPN1 is phosphorylated by mitotic kinases at four specific sites during mitosis, a time when nucleoplasm
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ONECUT2 acts as a lineage plasticity driver in adenocarcinoma as well as neuroendocrine variants of prostate cancer Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-27 Chen Qian, Qian Yang, Mirja Rotinen, Rongrong Huang, Hyoyoung Kim, Brad Gallent, Yiwu Yan, Radu M Cadaneanu, Baohui Zhang, Salma Kaochar, Stephen J Freedland, Edwin M Posadas, Leigh Ellis, Dolores Di Vizio, Colm Morrissey, Peter S Nelson, Lauren Brady, Ramachandran Murali, Moray J Campbell, Wei Yang, Beatrice S Knudsen, Elahe A Mostaghel, Huihui Ye, Isla P Garraway, Sungyong You, Michael R Freeman
Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) and the NE splicing factor SRRM4, which are key drivers
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Functional analysis of protein interactions using coupled bi-fluorescence complementation/GFP nanobody techniques Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-27 Tetsuaki Miyake, John C McDermott
Transcription factors (TFs) form homo- or hetero-dimeric DNA binding complexes along with associated co-regulators that can have transcriptional repressor or activator functions. Defining the specific composition of the complexes is therefore key to understanding their biological role. Here, we utilized bimolecular fluorescence complementation (BiFC) to visualize the formation of defined TF dimers
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Coordinated DNA polymerization by Polγ and the region of LonP1 regulated proteolysis Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-27 Amanda A Riccio, Asia J Brannon, Juno M Krahn, Jonathan Bouvette, Jason G Williams, Mario J Borgnia, William C Copeland
The replicative mitochondrial DNA polymerase, Polγ, and its protein regulation are essential for the integrity of the mitochondrial genome. The intricacies of Polγ regulation and its interactions with regulatory proteins, which are essential for fine-tuning polymerase function, remain poorly understood. Misregulation of the Polγ heterotrimer, consisting of (i) PolG, the polymerase catalytic subunit
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CLEMENT: genomic decomposition and reconstruction of non-tumor subclones Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-26 Young-soo Chung, Seungseok Kang, Jisu Kim, Sangbo Lee, Sangwoo Kim
Genome-level clonal decomposition of a single specimen has been widely studied; however, it is mostly limited to cancer research. In this study, we developed a new algorithm CLEMENT, which conducts accurate decomposition and reconstruction of multiple subclones in genome sequencing of non-tumor (normal) samples. CLEMENT employs the Expectation-Maximization (EM) algorithm with optimization strategies
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Multiplexed sequential imaging in living cells with orthogonal fluorogenic RNA aptamer/dye pairs Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-26 Ru Zheng, Rigumula Wu, Yuanchang Liu, Zhining Sun, Zhaolin Xue, Yousef Bagheri, Sima Khajouei, Lan Mi, Qian Tian, Raymond Pho, Qinge Liu, Sidrat Siddiqui, Kewei Ren, Mingxu You
Detecting multiple targets in living cells is important in cell biology. However, multiplexed fluorescence imaging beyond two-to-three targets remains a technical challenge. Herein, we introduce a multiplexed imaging strategy, ‘sequential Fluorogenic RNA Imaging-Enabled Sensor’ (seqFRIES), which enables live-cell target detection via sequential rounds of imaging-and-stripping. In seqFRIES, multiple
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protoSpaceJAM: an open-source, customizable and web-accessible design platform for CRISPR/Cas insertional knock-in Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-26 Duo Peng, Madhuri Vangipuram, Joan Wong, Manuel D Leonetti
CRISPR/Cas-mediated knock-in of DNA sequences enables precise genome engineering for research and therapeutic applications. However, designing effective guide RNAs (gRNAs) and homology-directed repair (HDR) donors remains a bottleneck. Here, we present protoSpaceJAM, an open-source algorithm to automate and optimize gRNA and HDR donor design for CRISPR/Cas insertional knock-in experiments, currently
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DNA binding and bridging by human CtIP in the healthy and diseased states Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-26 Shreya Lokanathan Balaji, Sara De Bragança, Francisco Balaguer-Pérez, Sarah Northall, Oliver John Wilkinson, Clara Aicart-Ramos, Neeleema Seetaloo, Frank Sobott, Fernando Moreno-Herrero, Mark Simon Dillingham
The human DNA repair factor CtIP helps to initiate the resection of double-stranded DNA breaks for repair by homologous recombination, in part through its ability to bind and bridge DNA molecules. However, CtIP is a natively disordered protein that bears no apparent similarity to other DNA-binding proteins and so the structural basis for these activities remains unclear. In this work, we have used
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High-density resolution of the Kaposi's sarcoma associated herpesvirus transcriptome identifies novel transcript isoforms generated by long-range transcription and alternative splicing Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-26 Ritu Shekhar, Tina O'Grady, Netanya Keil, April Feswick, David A Moraga Amador, Scott A Tibbetts, Erik K Flemington, Rolf Renne
Kaposi's sarcoma-associated herpesvirus is the etiologic agent of Kaposi's sarcoma and two B-cell malignancies. Recent advancements in sequencing technologies have led to high resolution transcriptomes for several human herpesviruses that densely encode genes on both strands. However, for KSHV progress remained limited due to the overall low percentage of KSHV transcripts, even during lytic replication
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Resolution of ribosomal stalling by EF-P and ABCF ATPases YfmR and YkpA/YbiT Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-25 Hiraku Takada, Keigo Fujiwara, Gemma C Atkinson, Shinobu Chiba, Vasili Hauryliuk
Efficiency of protein synthesis on the ribosome is strongly affected by the amino acid composition of the assembled amino acid chain. Challenging sequences include proline-rich motifs as well as highly positively and negatively charged amino acid stretches. Members of the F subfamily of ABC ATPases (ABCFs) have been long hypothesised to promote translation of such problematic motifs. In this study
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MRNIP limits ssDNA gaps during replication stress Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-25 Laura G Bennett, Ellen G Vernon, Vithursha Thanendran, Caryl M Jones, Amelia Gamble, Christopher J Staples
Replication repriming by the specialized primase-polymerase PRIMPOL ensures the continuity of DNA synthesis during replication stress. PRIMPOL activity generates residual post-replicative single-stranded nascent DNA gaps, which are linked with mutagenesis and chemosensitivity in BRCA1/2-deficient models, and which are suppressed by replication fork reversal mediated by the DNA translocases SMARCAL1
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A comprehensive analysis of 3′UTRs in Caenorhabditis elegans Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-25 Emma Murari, Dalton Meadows, Nicholas Cuda, Marco Mangone
3′Untranslated regions (3′UTRs) are essential portions of genes containing elements necessary for pre-mRNA 3′end processing and are involved in post-transcriptional gene regulation. Despite their importance, they remain poorly characterized in eukaryotes. Here, we have used a multi-pronged approach to extract and curate 3′UTR data from 11533 publicly available datasets, corresponding to the entire
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Comparative analysis of RNA 3D structure prediction methods: towards enhanced modeling of RNA–ligand interactions Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-25 Chandran Nithin, Sebastian Kmiecik, Roman Błaszczyk, Julita Nowicka, Irina Tuszyńska
Accurate RNA structure models are crucial for designing small molecule ligands that modulate their functions. This study assesses six standalone RNA 3D structure prediction methods—DeepFoldRNA, RhoFold, BRiQ, FARFAR2, SimRNA and Vfold2, excluding web-based tools due to intellectual property concerns. We focus on reproducing the RNA structure existing in RNA-small molecule complexes, particularly on
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Refining the pool of RNA-binding domains advances the classification and prediction of RNA-binding proteins Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-25 Elsa Wassmer, Gergely Koppány, Malte Hermes, Sven Diederichs, Maïwen Caudron-Herger
From transcription to decay, RNA-binding proteins (RBPs) influence RNA metabolism. Using the RBP2GO database that combines proteome-wide RBP screens from 13 species, we investigated the RNA-binding features of 176 896 proteins. By compiling published lists of RNA-binding domains (RBDs) and RNA-related protein family (Rfam) IDs with lists from the InterPro database, we analyzed the distribution of the
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Zika virus non-coding RNAs antagonize antiviral responses by PKR-mediated translational arrest Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-25 Horacio M Pallarés, María Mora González López Ledesma, Santiago Oviedo-Rouco, Luciana A Castellano, Guadalupe S Costa Navarro, Ana J Fernández-Alvarez, María Josefina D’Andreiz, Victor Daniel Aldas-Bulos, Diego E Alvarez, Ariel A Bazzini, Andrea V Gamarnik
Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that causes severe outbreaks in human populations. ZIKV infection leads to the accumulation of small non-coding viral RNAs (known as sfRNAs) that are crucial for evasion of antiviral responses and for viral pathogenesis. However, the mechanistic understanding of how sfRNAs function remains incomplete. Here, we use recombinant ZIKVs and ribosome
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Aptamer binding footprints discriminate α-synuclein fibrillar polymorphs from different synucleinopathies Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-25 Alix Bouvier-Müller, Deborah Fourmy, Alexis Fenyi, Luc Bousset, Ronald Melki, Frédéric Ducongé
Synucleinopathies, including dementia with Lewy bodies (DLB), Parkinson's disease (PD), and multiple system atrophy (MSA), are characterized by the presence of α-synuclein (α-syn) aggregates in the central nervous system. Recent evidence suggests that the heterogeneity of synucleinopathies may be partly explained by the fact that patients may have different α-syn fibrillar polymorphs with structural
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DNA-controlled protein fluorescence: Design of aptamer-split peptide hetero-modulator for GFP to respond to intracellular ATP levels Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-25 Ki Sung Park, Hanvit Cha, Jia Niu, Hyongsok Tom Soh, Jin Hyup Lee, Seung Pil Pack
Enabling the precise control of protein functions with artificially programmed reaction patterns is beneficial for investigating biological processes. Although several strategies have been established that employ the programmability of nucleic acid, they have been limited to DNA hybridization without external stimuli or target binding. Here, we report an approach for the DNA-mediated control of the
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SUMO protease and proteasome recruitment at the nuclear periphery differently affect replication dynamics at arrested forks Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-25 Kamila Schirmeisen, Karel Naiman, Karine Fréon, Laetitia Besse, Shrena Chakraborty, Anissia Ait Saada, Antony M Carr, Karol Kramarz, Sarah A E Lambert
Nuclear pore complexes (NPCs) have emerged as genome organizers, defining a particular nuclear compartment enriched for SUMO protease and proteasome activities, and act as docking sites for the repair of DNA damage. In fission yeast, the anchorage of perturbed replication forks to NPCs is an integral part of the recombination-dependent replication restart mechanism (RDR) that resumes DNA synthesis
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Promoter dependent RNA polymerase II bypass of the epimerizable DNA lesion, Fapy•dG and 8-Oxo-2′-deoxyguanosine Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-22 Shijun Gao, Yuki Tahara, Eric T Kool, Marc M Greenberg
Formamidopyrimidine (Fapy•dG) is a major lesion arising from oxidation of dG that is produced from a common chemical precursor of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-OxodGuo). In human cells, replication of single-stranded shuttle vectors containing Fapy•dG is more mutagenic than 8-OxodGuo. Here, we present the first data regarding promoter dependent RNA polymerase II bypass of Fapy•dG. 8-OxodGuo
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Disordered sequences of transcription factors regulate genomic binding by integrating diverse sequence grammars and interaction types Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-22 Bohdana Hurieva, Divya Krishna Kumar, Rotem Morag, Offir Lupo, Miri Carmi, Naama Barkai, Felix Jonas
Intrinsically disordered regions (IDRs) guide transcription factors (TFs) to their genomic binding sites, raising the question of how structure-lacking regions encode for complex binding patterns. We investigated this using the TF Gln3, revealing sets of IDR-embedded determinants that direct Gln3 binding to respective groups of functionally related promoters, and enable tuning binding preferences between
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PBOX-sRNA-seq uncovers novel features of miRNA modification and identifies selected 5′-tRNA fragments bearing 2′-O-modification Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-22 Susu Chen, Yuchen Cai, Huiru Yang, Bin Zhang, Ning Li, Guodong Ren
The concomitant cloning of RNA degradation products is a major concern in standard small RNA-sequencing practices. This not only complicates the characterization of bona fide sRNAs but also hampers cross-batch experimental replicability and sometimes even results in library construction failure. Given that all types of plant canonical small RNAs possess the 3′ end 2′-O-methylation modification, a new
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A treasure trove of 1034 actinomycete genomes Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-22 Tue Sparholt Jørgensen, Omkar S Mohite, Eva B Sterndorff, Maria Alvarez-Arevalo, Kai Blin, Thomas J Booth, Pep Charusanti, David Faurdal, Troels Ø Hansen, Matin Nuhamunada, Anna-Sophie Mourched, Bernhard Ø Palsson, Tilmann Weber
Filamentous Actinobacteria, recently renamed Actinomycetia, are the most prolific source of microbial bioactive natural products. Studies on biosynthetic gene clusters benefit from or require chromosome-level assemblies. Here, we provide DNA sequences from >1000 isolates: 881 complete genomes and 153 near-complete genomes, representing 28 genera and 389 species, including 244 likely novel species.
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Differential impact of quiescent non-coding loci on chromatin entropy Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-22 Peiyao Wu, Mina Yao, Wei Wang
Non-coding regions of the human genome are important for functional regulations, but their mechanisms remain elusive. We used machine learning to guide a CRISPR screening on hubs (i.e. non-coding loci forming many 3D contacts) and significantly increased the discovery rate of hubs essential for cell growth. We found no clear genetic or epigenetic differences between essential and nonessential hubs
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iMab antibody binds single-stranded cytosine-rich sequences and unfolds DNA i-motifs Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-22 Joseph Boissieras, Hugues Bonnet, Maria Fidelia Susanto, Dennis Gomez, Eric Defrancq, Anton Granzhan, Jérôme Dejeu
i-Motifs (iMs) are non-canonical, four-stranded secondary structures formed by stacking of hemi-protonated CH+·C base pairs in cytosine-rich DNA sequences, predominantly at pH < 7. The presence of iM structures in cells was a matter of debate until the recent development of iM-specific antibody, iMab, which was instrumental for several studies that suggested the existence of iMs in live cells and their
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Phase-separated ParB enforces diverse DNA compaction modes and stabilizes the parS-centered partition complex Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-22 Yilin Zhao, Lijuan Guo, Jiaojiao Hu, Zhiyun Ren, Yanan Li, Meng Hu, Xia Zhang, Lulu Bi, Dan Li, Hanhui Ma, Cong Liu, Bo Sun
The tripartite ParABS system mediates chromosome segregation in the majority of bacterial species. Typically, DNA-bound ParB proteins around the parS sites condense the chromosomal DNA into a higher-order multimeric nucleoprotein complex for the ParA-driven partition. Despite extensive studies, the molecular mechanism underlying the dynamic assembly of the partition complex remains unclear. Herein
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HDAC4 influences the DNA damage response and counteracts senescence by assembling with HDAC1/HDAC2 to control H2BK120 acetylation and homology-directed repair Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-14 Eros Di Giorgio, Emiliano Dalla, Vanessa Tolotto, Francesca D’Este, Harikrishnareddy Paluvai, Liliana Ranzino, Claudio Brancolini
Access to DNA is the first level of control in regulating gene transcription, a control that is also critical for maintaining DNA integrity. Cellular senescence is characterized by profound transcriptional rearrangements and accumulation of DNA lesions. Here, we discovered an epigenetic complex between HDAC4 and HDAC1/HDAC2 that is involved in the erase of H2BK120 acetylation. The HDAC4/HDAC1/HDAC2
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Efficient activation of hundreds of LTR12C elements reveals cis-regulatory function determined by distinct epigenetic mechanisms Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-14 Hitoshi Ohtani, Minmin Liu, Gangning Liang, H Josh Jang, Peter A Jones
Long terminal repeats (LTRs), which often contain promoter and enhancer sequences of intact endogenous retroviruses (ERVs), are known to be co-opted as cis-regulatory elements for fine-tuning host-coding gene expression. Since LTRs are mainly silenced by the deposition of repressive epigenetic marks, substantial activation of LTRs has been found in human cells after treatment with epigenetic inhibitors
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The impact of mRNA poly(A) tail length on eukaryotic translation stages Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-14 Nikita Biziaev, Alexey Shuvalov, Ali Salman, Tatiana Egorova, Ekaterina Shuvalova, Elena Alkalaeva
The poly(A) tail plays an important role in maintaining mRNA stability and influences translation efficiency via binding with PABP. However, the impact of poly(A) tail length on mRNA translation remains incompletely understood. This study explores the effects of poly(A) tail length on human translation. We determined the translation rates in cell lysates using mRNAs with different poly(A) tails. Cap-dependent
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Intrinsically disordered regions regulate RhlE RNA helicase functions in bacteria Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-14 Stéphane Hausmann, Johan Geiser, George Edward Allen, Sandra Amandine Marie Geslain, Martina Valentini
RNA helicases—central enzymes in RNA metabolism—often feature intrinsically disordered regions (IDRs) that enable phase separation and complex molecular interactions. In the bacterial pathogen Pseudomonas aeruginosa, the non-redundant RhlE1 and RhlE2 RNA helicases share a conserved REC catalytic core but differ in C-terminal IDRs. Here, we show how the IDR diversity defines RhlE RNA helicase specificity
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Cooperative Gsx2–DNA binding requires DNA bending and a novel Gsx2 homeodomain interface Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-14 Jordan A Webb, Edward Farrow, Brittany Cain, Zhenyu Yuan, Alexander E Yarawsky, Emma Schoch, Ellen K Gagliani, Andrew B Herr, Brian Gebelein, Rhett A Kovall
The conserved Gsx homeodomain (HD) transcription factors specify neural cell fates in animals from flies to mammals. Like many HD proteins, Gsx factors bind A/T-rich DNA sequences prompting the following question: How do HD factors that bind similar DNA sequences in vitro regulate specific target genes in vivo? Prior studies revealed that Gsx factors bind DNA both as a monomer on individual A/T-rich
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Formation of left-handed helices by C2′-fluorinated nucleic acids under physiological salt conditions Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-13 Roberto El-Khoury, Cristina Cabrero, Santiago Movilla, Harneesh Kaur, David Friedland, Arnau Domínguez, James D Thorpe, Morgane Roman, Modesto Orozco, Carlos González, Masad J Damha
Recent findings in cell biology have rekindled interest in Z-DNA, the left-handed helical form of DNA. We report here that two minimally modified nucleosides, 2′F-araC and 2′F-riboG, induce the formation of the Z-form under low ionic strength. We show that oligomers entirely made of these two nucleosides exclusively produce left-handed duplexes that bind to the Zα domain of ADAR1. The effect of the
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FRET-guided modeling of nucleic acids Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-13 Fabio D Steffen, Richard A Cunha, Roland K O Sigel, Richard Börner
The functional diversity of RNAs is encoded in their innate conformational heterogeneity. The combination of single-molecule spectroscopy and computational modeling offers new attractive opportunities to map structural transitions within nucleic acid ensembles. Here, we describe a framework to harmonize single-molecule Förster resonance energy transfer (FRET) measurements with molecular dynamics simulations
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Eukaryotic AlaX provides multiple checkpoints for quality and quantity of aminoacyl-tRNAs in translation Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-13 Zi-Han Li, Xiao-Long Zhou
Translational fidelity relies critically on correct aminoacyl-tRNA supply. The trans-editing factor AlaX predominantly hydrolyzes Ser-tRNAAla, functioning as a third sieve of alanyl-tRNA synthetase (AlaRS). Despite extensive studies in bacteria and archaea, the mechanism of trans-editing in mammals remains largely unknown. Here, we show that human AlaX (hAlaX), which is exclusively distributed in the
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Apollon: a deoxyribozyme that generates a yellow product Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-13 Martin Volek, Jaroslav Kurfürst, Milan Kožíšek, Pavel Srb, Václav Veverka, Edward A Curtis
Colorimetric assays in which the color of a solution changes in the presence of an input provide a simple and inexpensive way to monitor experimental readouts. In this study we used in vitro selection to identify a self-phosphorylating kinase deoxyribozyme that produces a colorimetric signal by converting the colorless substrate pNPP into the yellow product pNP. The minimized catalytic core, sequence
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YY1 is involved in homologous recombination inhibition at guanine quadruplex sites in human cells Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-13 Xinyu Cui, Chengwen Zhang, Chunqing Fu, Jinglei Hu, Tengjiao Li, Lin Li
Homologous recombination (HR) is a key process for repairing DNA double strand breaks and for promoting genetic diversity. However, HR occurs unevenly across the genome, and certain genomic features can influence its activity. One such feature is the presence of guanine quadruplexes (G4s), stable secondary structures widely distributed throughout the genome. These G4s play essential roles in gene transcription
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Engineering spacer specificity of the Cre/loxP system Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-13 Jenna Hoersten, Gloria Ruiz-Gómez, Maciej Paszkowski-Rogacz, Giorgio Gilioli, Pedro Manuel Guillem-Gloria, Felix Lansing, M Teresa Pisabarro, Frank Buchholz
Translational research on the Cre/loxP recombination system focuses on enhancing its specificity by modifying Cre/DNA interactions. Despite extensive efforts, the exact mechanisms governing Cre discrimination between substrates remains elusive. Cre recognizes 13 bp inverted repeats, initiating recombination in the 8 bp spacer region. While literature suggests that efficient recombination proceeds between
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Concerted action of ataxin-2 and PABPC1-bound mRNA poly(A) tail in the formation of stress granules Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-13 Ryota Yamagishi, Hiroto Inagaki, Jun Suzuki, Nao Hosoda, Haruka Sugiyama, Kazunori Tomita, Takashi Hotta, Shin-ichi Hoshino
Stress induces global stabilization of the mRNA poly(A) tail (PAT) and the assembly of untranslated poly(A)-tailed mRNA into mRNPs that accumulate in stress granules (SGs). While the mechanism behind stress-induced global PAT stabilization has recently emerged, the biological significance of PAT stabilization under stress remains elusive. Here, we demonstrate that stress-induced PAT stabilization is
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Staphylococcal aconitase expression during iron deficiency is controlled by an sRNA-driven feedforward loop and moonlighting activity Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-13 Maxime Barrault, Svetlana Chabelskaya, Rodrigo H Coronel-Tellez, Claire Toffano-Nioche, Eric Jacquet, Philippe Bouloc
Pathogenic bacteria employ complex systems to cope with metal ion shortage conditions and propagate in the host. IsrR is a regulatory RNA (sRNA) whose activity is decisive for optimum Staphylococcus aureus fitness upon iron starvation and for full virulence. IsrR down-regulates several genes encoding iron-containing enzymes to spare iron for essential processes. Here, we report that IsrR regulates
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Maf1 phosphorylation is regulated through the action of prefoldin-like Bud27 on PP4 phosphatase in Saccharomyces cerevisiae Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-12 Francisco Gutiérrez-Santiago, Verónica Martínez-Fernández, Ana Isabel Garrido-Godino, Cristina Colino-Palomino, Andrés Clemente-Blanco, Christine Conesa, Joël Acker, Francisco Navarro
Bud27 is a prefoldin-like protein that participates in transcriptional regulation mediated by the three RNA polymerases in Saccharomyces cerevisiae. Lack of Bud27 significantly affects RNA pol III transcription, although the involved mechanisms have not been characterized. Here, we show that Bud27 regulates the phosphorylation state of the RNA pol III transcriptional repressor, Maf1, influences its
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Loops are geometric catalysts for DNA integration Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-12 Cleis Battaglia, Davide Michieletto
The insertion of DNA elements within genomes underpins both genetic diversity and disease when unregulated. Most of DNA insertions are not random and the physical mechanisms underlying the integration site selection are poorly understood. Here, we perform Molecular Dynamics simulations to study the insertion of DNA elements, such as viral DNA or transposons, into naked DNA or chromatin substrates.
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Aurora: a fluorescent deoxyribozyme for high-throughput screening Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-11 Martin Volek, Jaroslav Kurfürst, Matúš Drexler, Michal Svoboda, Pavel Srb, Václav Veverka, Edward A Curtis
Fluorescence facilitates the detection, visualization, and tracking of molecules with high sensitivity and specificity. A functional DNA molecule that generates a robust fluorescent signal would offer significant advantages for many applications compared to intrinsically fluorescent proteins, which are expensive and labor intensive to synthesize, and fluorescent RNA aptamers, which are unstable under
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OptoLacI: optogenetically engineered lactose operon repressor LacI responsive to light instead of IPTG Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-11 Meizi Liu, Zuhui Li, Jianfeng Huang, Junjun Yan, Guoping Zhao, Yanfei Zhang
Optogenetics’ advancement has made light induction attractive for controlling biological processes due to its advantages of fine-tunability, reversibility, and low toxicity. The lactose operon induction system, commonly used in Escherichia coli, relies on the binding of lactose or isopropyl β-d-1-thiogalactopyranoside (IPTG) to the lactose repressor protein LacI, playing a pivotal role in controlling
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Crystal structure of a tetrameric RNA G-quadruplex formed by hexanucleotide repeat expansions of C9orf72 in ALS/FTD Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-11 Yanyan Geng, Changdong Liu, Naining Xu, Monica Ching Suen, Haitao Miao, Yuanyuan Xie, Bingchang Zhang, Xueqin Chen, Yuanjian Song, Zhanxiang Wang, Qixu Cai, Guang Zhu
The abnormal GGGGCC hexanucleotide repeat expansions (HREs) in C9orf72 cause the fatal neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal dementia. The transcribed RNA HREs, short for r(G4C2)n, can form toxic RNA foci which sequestrate RNA binding proteins and impair RNA processing, ultimately leading to neurodegeneration. Here, we determined the crystal structure
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KDM6A–SND1 interaction maintains genomic stability by protecting the nascent DNA and contributes to cancer chemoresistance Nucleic Acids Res. (IF 16.6) Pub Date : 2024-06-08 Jian Wu, Yixin Jiang, Qin Zhang, Xiaobing Mao, Tong Wu, Mengqiu Hao, Su Zhang, Yang Meng, Xiaowen Wan, Lei Qiu, Junhong Han
Genomic instability is one of the hallmarks of cancer. While loss of histone demethylase KDM6A increases the risk of tumorigenesis, its specific role in maintaining genomic stability remains poorly understood. Here, we propose a mechanism in which KDM6A maintains genomic stability independently on its demethylase activity. This occurs through its interaction with SND1, resulting in the establishment
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Genomic context-dependent histone H3K36 methylation by three Drosophila methyltransferases and implications for dedicated chromatin readers Nucleic Acids Res. (IF 16.6) Pub Date : 2024-05-30 Muhunden Jayakrishnan, Magdalena Havlová, Václav Veverka, Catherine Regnard, Peter B Becker
Methylation of histone H3 at lysine 36 (H3K36me3) marks active chromatin. The mark is interpreted by epigenetic readers that assist transcription and safeguard the integrity of the chromatin fiber. The chromodomain protein MSL3 binds H3K36me3 to target X-chromosomal genes in male Drosophila for dosage compensation. The PWWP-domain protein JASPer recruits the JIL1 kinase to active chromatin on all chromosomes
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CGeNArate: a sequence-dependent coarse-grained model of DNA for accurate atomistic MD simulations of kb-long duplexes Nucleic Acids Res. (IF 16.6) Pub Date : 2024-05-30 David Farré-Gil, Juan Pablo Arcon, Charles A Laughton, Modesto Orozco
We present CGeNArate, a new model for molecular dynamics simulations of very long segments of B-DNA in the context of biotechnological or chromatin studies. The developed method uses a coarse-grained Hamiltonian with trajectories that are back-mapped to the atomistic resolution level with extreme accuracy by means of Machine Learning Approaches. The method is sequence-dependent and reproduces very
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Generating, modeling and evaluating a large-scale set of CRISPR/Cas9 off-target sites with bulges Nucleic Acids Res. (IF 16.6) Pub Date : 2024-05-30 Ofir Yaish, Yaron Orenstein
The CRISPR/Cas9 system is a highly accurate gene-editing technique, but it can also lead to unintended off-target sites (OTS). Consequently, many high-throughput assays have been developed to measure OTS in a genome-wide manner, and their data was used to train machine-learning models to predict OTS. However, these models are inaccurate when considering OTS with bulges due to limited data compared
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mosaicMPI: a framework for modular data integration across cohorts and -omics modalities Nucleic Acids Res. (IF 16.6) Pub Date : 2024-05-30 Theodore B Verhey, Heewon Seo, Aaron Gillmor, Varsha Thoppey-Manoharan, David Schriemer, Sorana Morrissy
Advances in molecular profiling have facilitated generation of large multi-modal datasets that can potentially reveal critical axes of biological variation underlying complex diseases. Distilling biological meaning, however, requires computational strategies that can perform mosaic integration across diverse cohorts and datatypes. Here, we present mosaicMPI, a framework for discovery of low to high-resolution
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The developmental and evolutionary characteristics of transcription factor binding site clustered regions based on an explainable machine learning model Nucleic Acids Res. (IF 16.6) Pub Date : 2024-05-30 Zhangyi Ouyang, Feng Liu, Wanying Li, Junting Wang, Bijia Chen, Yang Zheng, Yaru Li, Huan Tao, Xiang Xu, Cheng Li, Yuwen Cong, Hao Li, Xiaochen Bo, Hebing Chen
Gene expression is temporally and spatially regulated by the interaction of transcription factors (TFs) and cis-regulatory elements (CREs). The uneven distribution of TF binding sites across the genome poses challenges in understanding how this distribution evolves to regulate spatio-temporal gene expression and consequent heritable phenotypic variation. In this study, chromatin accessibility profiles
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Biochemical properties of chromatin domains define genome compartmentalization Nucleic Acids Res. (IF 16.6) Pub Date : 2024-05-29 Federica Lucini, Cristiano Petrini, Elisa Salviato, Koustav Pal, Valentina Rosti, Francesca Gorini, Philina Santarelli, Roberto Quadri, Giovanni Lembo, Giulia Graziano, Emanuele Di Patrizio Soldateschi, Ilario Tagliaferri, Eva Pinatel, Endre Sebestyén, Luca Rotta, Francesco Gentile, Valentina Vaira, Chiara Lanzuolo, Francesco Ferrari
Chromatin three-dimensional (3D) organization inside the cell nucleus determines the separation of euchromatin and heterochromatin domains. Their segregation results in the definition of active and inactive chromatin compartments, whereby the local concentration of associated proteins, RNA and DNA results in the formation of distinct subnuclear structures. Thus, chromatin domains spatially confined
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Bioinformatic analysis of type III CRISPR systems reveals key properties and new effector families Nucleic Acids Res. (IF 16.6) Pub Date : 2024-05-29 Ville Hoikkala, Shirley Graham, Malcolm F White
Recognition of RNA from invading mobile genetic elements (MGE) prompts type III CRISPR systems to activate an HD nuclease domain and/or a nucleotide cyclase domain in the Cas10 subunit, eliciting an immune response. The cyclase domain can generate a range of nucleotide second messengers, which in turn activate a diverse family of ancillary effector proteins. These provide immunity by non-specific degradation
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LowTempGAL: a highly responsive low temperature-inducible GAL system in Saccharomyces cerevisiae Nucleic Acids Res. (IF 16.6) Pub Date : 2024-05-29 Zeyu Lu, Qianyi Shen, Naga Chandra Bandari, Samuel Evans, Liam McDonnell, Lian Liu, Wanli Jin, Carlos Horacio Luna-Flores, Thomas Collier, Gert Talbo, Tim McCubbin, Lygie Esquirol, Chris Myers, Matt Trau, Geoff Dumsday, Robert Speight, Christopher B Howard, Claudia E Vickers, Bingyin Peng
Temperature is an important control factor for biologics biomanufacturing in precision fermentation. Here, we explored a highly responsive low temperature-inducible genetic system (LowTempGAL) in the model yeast Saccharomyces cerevisiae. Two temperature biosensors, a heat-inducible degron and a heat-inducible protein aggregation domain, were used to regulate the GAL activator Gal4p, rendering the leaky
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Pseudogenes in plasmid genomes reveal past transitions in plasmid mobility Nucleic Acids Res. (IF 16.6) Pub Date : 2024-05-29 Dustin M Hanke, Yiqing Wang, Tal Dagan
Evidence for gene non-functionalization due to mutational processes is found in genomes in the form of pseudogenes. Pseudogenes are known to be rare in prokaryote chromosomes, with the exception of lineages that underwent an extreme genome reduction (e.g. obligatory symbionts). Much less is known about the frequency of pseudogenes in prokaryotic plasmids; those are genetic elements that can transfer
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WebGestalt 2024: faster gene set analysis and new support for metabolomics and multi-omics Nucleic Acids Res. (IF 16.6) Pub Date : 2024-05-29 John M Elizarraras, Yuxing Liao, Zhiao Shi, Qian Zhu, Alexander R Pico, Bing Zhang
Enrichment analysis, crucial for interpreting genomic, transcriptomic, and proteomic data, is expanding into metabolomics. Furthermore, there is a rising demand for integrated enrichment analysis that combines data from different studies and omics platforms, as seen in meta-analysis and multi-omics research. To address these growing needs, we have updated WebGestalt to include enrichment analysis capabilities
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PHF2 regulates genome topology and DNA replication in neural stem cells via cohesin Nucleic Acids Res. (IF 16.6) Pub Date : 2024-05-29 Jia Feng, You Heng Chuah, Yajing Liang, Nadia Omega Cipta, Yingying Zeng, Tushar Warrier, Gamal Ahmed Rashed Elsayed Elfar, Jeehyun Yoon, Oleg V Grinchuk, Emmy Xue Yun Tay, Ker-Zhing Lok, Zong-Qing Zheng, Zi Jian Khong, Zheng-Shan Chong, Jackie Teo, Emma May Sanford, Cheryl Jia Yi Neo, Hsin Yao Chiu, Jia Yu Leung, Loo Chien Wang, Yan Ting Lim, Tianyun Zhao, Radoslaw M Sobota, Karen Carmelina Crasta
Cohesin plays a crucial role in the organization of topologically-associated domains (TADs), which influence gene expression and DNA replication timing. Whether epigenetic regulators may affect TADs via cohesin to mediate DNA replication remains elusive. Here, we discover that the histone demethylase PHF2 associates with RAD21, a core subunit of cohesin, to regulate DNA replication in mouse neural