Stepwise DNA-unwinding gates TnpB genome-editing activity

Zhou, Saffarian-Deemyad, Shi, Weiss, et al. show that Ymu1 TnpB unwinds DNA through a stepwise pathway with a metastable intermediate. Engineered mutations that stabilize specific unwinding states accelerate cleavage and enhance editing activity in plants, establishing a framework for engineering compact RNA-guided nucleases.

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PALM-Scan enables single-molecule site-specific detection of protein S-palmitoylation with a nanopore

Accurate S-palmitoylation detection at cellular and tissue levels remains challenging. Zhang et al. develop PALM-Scan, a nanopore platform that directly reads S-palmitoylation on peptides. This label-free method monitors depalmitoylation kinetics in real time, distinguishes competing cysteine modifications, and detects palmitoylated disease biomarkers from serum samples, thereby providing a transformative tool for studying protein S-palmitoylation in health and disease.

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LZTFL1 rewires NADPH-glutathione metabolism to amplify ferroptosis

Xue et al. identify LZTFL1 as a key regulator of ferroptosis that rewires GSH metabolism by promoting G6PD oxidation. GSH depletion enhances LZTFL1 translation, forming a feedforward circuit that amplifies ferroptosis. Restoring LZTFL1 re-sensitizes cisplatin-resistant tumors, highlighting its potential as a biomarker and therapeutic target.

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Torsins organize CLCC1 assembly to safeguard ER bilayer and lipid homeostasis

Chen and colleagues identify CLCC1 as the functional substrate downstream of torsin AAA+ ATPases. TorsinA depletion disrupts CLCC1’s oligomeric state and triggers massive lipid deposition within the ER. Importantly, ectopic expression of CLCC1 overcomes torsinA loss and fully reverses the lipid mis-deposition.

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The dystonia-associated Torsin1A sustains CLCC1 function in membrane fusion of the nuclear envelope for NPC biogenesis

Maslennikova et al. identify the ER membrane protein CLCC1 as an interaction partner of the dystonia-linked AAA+ ATPase Torsin1A. Torsin1A sustains the function of CLCC1, which is proposed to facilitate fusion of the nuclear envelope during NPC biogenesis by forming an oligomer that promotes lipid bilayer approach and remodeling.

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METTL3 promotes cell-cycle progression via activation of transcriptional elongation

Akçaöz-Alasar et al. reveal that the mitotic kinase CDK1 phosphorylates the m6A methyltransferase METTL3, which then methylates 7SK RNA to release P-TEFb and promote RNA polymerase II clearance during mitosis, ensuring proper chromosome segregation.

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Escaping our own biases: AI, scientific reasoning, and discovery in molecular biology

Artificial intelligence may transform molecular biology not by always providing the correct answer, but by exploring mechanistic possibilities unconstrained by the assumptions that shape expert thinking. Its greatest contribution may be exposing the intellectual blind spots of scientists, while experimental validation remains the ultimate arbiter of truth.

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Distinct sources and effects of mitochondrial reactive oxygen species

Mitochondrial reactive oxygen species (mtROS) serve many cellular roles, and emerging evidence points to individual sources of mitochondrial ROS (ISOMRs) as separately regulated and localized contributors. This review explores ISOMRs and their distinct functional effects across different cell types and biological and pathological contexts.

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Biomolecular condensates can function as inherent catalysts

Chen, Guo, Farag, Qian et al. present that biomolecular condensates formed by proteins lacking catalytic activity can mediate diverse hydrolysis reactions, highlighting the importance of condensate electrochemical environments in regulating condensate biochemistry.

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The Legionella pneumophila effector SidL is an adenylyltransferase that modifies the glycolytic intermediate 3-phosphoglycerate

Black et al. identify the L. pneumophila effector SidL as an adenylyltransferase that targets host glycolysis. SidL covalently modifies the glycolytic intermediate 3-phosphoglycerate (3PG) with AMP, generating the previously unknown metabolite 2-AMP-3-phosphoglycerate (2-AMP-3PG), while simultaneously preventing the use of 3PG in eukaryotic metabolism.

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Du métabolisme à la dégradation des protéines: un nouveau rôle pour l'hème

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DeorphaNN: Virtual screening of GPCR peptide agonists using AlphaFold-predicted active-state complexes and deep learning embeddings

Ferguson et al. develop DeorphaNN, a graph neural network integrating active-state GPCR-peptide structural predictions, interatomic interactions, and deep learning embeddings to prioritize putative peptide agonists for experimental screening. DeorphaNN improves agonist prioritization over AlphaFold and general protein-protein interaction models.

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BRD4: From molecular understanding to therapeutics development

Bromodomain-containing protein 4 (BRD4) is an important therapeutic target for anticancer, antiviral, and anti-inflammatory responses. In this review, Wu and Chiang discuss how BRD4, as a universal epigenetic regulator, is tailored for context-specific gene regulation and highlight the importance of protein isoforms and posttranslational modifications, particularly phosphorylation, in generating protein diversity and further in developing phospho-BRD4 IDR-targeting compounds as new therapeutic agents.

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Nascent chain folding status modulates ribosome dynamics and mRNA stability through the ribosome-associated chaperone Zuo1

Chang et al. show that co-translational protein misfolding feeds back to ribosomes, slowing translation elongation and triggering mRNA decay. The ribosome-associated chaperone Zuo1 mediates this response, coupling nascent protein folding status to mRNA stability via the Ccr4–Not complex—a surveillance mechanism conserved from yeast to humans.

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Temporal control of macrophage pro-inflammatory phenotype by a biphasic HIF-1α regulatory program

Davanzo et al. identify a biphasic HIF-1α program in macrophage activation. Early HIF-1α stabilization depends on a RUBCN-NOX2-ROS axis operating independently of canonical and non-canonical autophagy, driving inflammatory and glycolytic programs, whereas late HIF-1α-iNOS-NO signaling drives mitochondrial dysfunction. These findings redefine how macrophage metabolism and inflammatory responses are temporally coordinated.

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Yeast Rad55–Rad57–SHU paralog complex dynamically promotes Rad51 filament formation

Koo et al. show how the yeast Rad51 paralog complex Rad55–Rad57–SHU promotes homologous recombination. Cryo-EM structures reveal that Rad55–Rad57 recruits Rad51 to ssDNA to seed filament formation, while ATP hydrolysis promotes paralog complex turnover.

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Host transcriptional corepressor TLE1 is commonly exploited by RNA viruses for replication

Yang et al. reveal that IAV and SARS-CoV-2 hijack host TLE1 via a conserved bHLH-like motif to recruit KLF4, boosting viral replication and suppressing innate immunity. Peptide AH49A blocks host-virus interaction and inhibits viral replication, which represents a conserved mechanism across different RNA viruses and potentially a broad-spectrum antiviral strategy.

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The +1 nucleosome functions in RNA Pol II transcription initiation and the transition to elongation

By combining biochemical assays and electron cryo-microscopy, Zhan, Abril-Garrido, et al. elucidated key steps of transcription initiation and the transition to elongation in the presence of the +1 nucleosome. The authors demonstrated for the first time that the +1 nucleosome has an active role in the initiation-elongation transition.

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Uridine cytidine kinase 1 promotes phosphatidylcholine biosynthesis, facilitating SARS-CoV-2 infection

Although UCK1 and UCK2 are considered functionally redundant isozymes catalyzing the rate-limiting step of pyrimidine salvage, Shi et al. discovered a noncanonical role of UCK1 contributing to phosphatidylcholine metabolism by dissecting their roles in SARS-CoV-2 infection. Comparative lipidomics also pinpointed specific lipid species and peroxisomal activities required for SARS-CoV-2 replication.

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Mechanism of MEK1 phosphorylation by the N-terminal acidic motif-mediated asymmetric BRAF dimer

Kondo, Notbohm, et al. show that the BRAF N-terminal acidic motif engages the dimeric interface to drive an asymmetric arrangement in which only one protomer adopts a canonical active kinase conformation. Captured MEK1 Ser222 phosphorylation and mutational analysis corroborate that this motif is required for full BRAF kinase activity.

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Disruption of microhomology-mediated end joining in Ewing sarcoma

Asada et al. show that EWS-FLI1 disrupts EWSR1-dependent POLQ pre-mRNA splicing, causing Polθ loss and MMEJ deficiency in Ewing sarcoma. This repair defect creates synthetic lethal vulnerabilities to FA, HR, and NHEJ pathway inhibition, revealing actionable therapeutic strategies.

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Structures of dynamic interactors at native proteasomes by PhIX-MS and cryo-electron microscopy

Lee et al. developed PhIX-MS, a UV-activated crosslinking structural proteomics workflow that traps transient interactions in cells to provide residue-to-residue distance information. These data are integrated with AlphaFold and/or cryo-EM to solve structures of the 26S or 19S proteasome bound to transient interactors, notably UBE3C, PSMD5, and TXNL1.

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RNA exonuclease REXO4 resolves m6A-marked R-loops and suppresses anti-tumor immunity

Zhang et al. reveal that the RNA exonuclease REXO4, guided by m6A modification, sustains R-loop homeostasis and genome integrity. Genetic loss or pharmacological inhibition of REXO4 triggers immunogenic interferon signaling and tumor immune infiltration, creating a synergistic vulnerability to PD-1 checkpoint inhibition in squamous cell carcinoma.

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Thyroid cancer-associated EZH1 Q571R mutation drives chromatin compaction and H3K27me3 invasion into active chromatin

Kim et al. show that the thyroid cancer-associated EZH1 Q571R mutation uniquely compacts chromatin, enhances histone methyltransferase activity, and drives H3K27me3 spreading into H3K36me2 regions. Unlike the equivalent EZH2 mutation, EZH1 Q571R-dependent chromatin compaction is essential for epigenetic reprogramming, revealing a fundamental mechanistic divergence between EZH1 and EZH2 mutants.

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Genome-wide rotational and translational phasing of nucleosomes with human transcription factors

Chen et al. introduce Benzonase-seq and ChIP-exo v6 to measure nucleosome rotational and translational phasing at genomic transcription factor binding sites. Sites were found to be either rotationally exposed or buried on the nucleosome. Transcription factor binding imposes a global canonical phase on adjacent nucleosomes, which can be DNA encoded.

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Biomolecular condensates for proteostasis and potential therapeutic applications

LLPS-driven condensates are emerging as central regulators of proteostasis. This perspective examines their assembly and physiological functions, highlighting how these condensates can be harnessed to eliminate “undruggable” targets and reestablish proteostasis for precision medicine across a range of major diseases.

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Large-scale tethered screen of RNA-binding proteins reveals novel regulators of poly(A) site selection

Jagannatha et al. use a large-scale tethering screen to systematically identify RNA-binding proteins (RBPs) that regulate alternative polyadenylation, build a sequence-based model that predicts poly(A) site-selection activators, and uncover direct links between GRB2, RNPS1, and the cleavage and polyadenylation machinery.

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Structures of the PI3Kα/KRas complex on lipid bilayers reveal molecular mechanisms of PI3Kα activation

Torosyan et al. reveal how a phospholipid bilayer, PIP2, KRas, and a receptor tyrosine kinase-derived phosphopeptide progressively activate PI3Kα, culminating in its dimerization, which boosts Akt signaling. The work provides a structural framework for understanding pathway regulation and highlights new opportunities for targeting PI3Kα-driven disease.

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