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Genomic integration of DNA templates is made more precise through microhomology-focused design.

The EWSR1::FLI1 fusion protein is the oncogenic driver of Ewing sarcoma (EwS). Here, the authors find that EWSR1::FLI1 plays a non-canonical role in mRNA decay via interactions with the CCR4-NOT deadenylation complex and the RNA-binding protein HuR. This role uncovers a new therapeutic vulnerability of EwS to HuR inhibition.

Mauthe et al. find that protein aggregate clearance requires fragmentation of the aggregate by a chaperone module and a proteasomal regulatory particle for recruitment and clustering of selective autophagy receptors to initiate phagophore formation.

Post-translational modifications (PTMs) are important for the stability and function of many therapeutic proteins. Here, the authors develop a high-throughput workflow combining cell-free gene expression with AlphaLISA to rapidly characterize and engineer PTMs on both proteins and peptides.

The authors present PIONEAR–seq technology to assay in vitro binding of pioneer transcription factors to nucleosomes. The PIONEAR–seq data reveal that a nucleosome’s broader sequence context regulates the interactions of pioneer transcription factors via DNA bendability.

Here the authors identify RNA G-quadruplexes as temperature-sensitive regulators of alternative splicing and gene expression, opening potential therapeutic avenues such as neuroprotection with potassium channel blockers.

DNA replication stress is a driver of genome instability. Here, the authors identify a role of the E3 ligase RNF25 in promoting replication stress tolerance. Mechanistically, RNF25 recruits the fork protection factor REV7 to stalled replication forks and prevents nucleolytic degradation.

Prenatal stress triggers molecular dysregulations in fetal neuroimmune circuits, leading to altered mast cell and sensory neuron function, which predisposes offspring to develop eczema in response to otherwise harmless mechanical friction after birth.

The mechanism of macrophage cytotoxicity against cancer cells requires further illustration. By employing CRISPR screening in CAR-macrophage and cancer cell co-culture system, the authors identify depletion of ATG9A on cancer cells sensitizes them to macrophage-mediated killing, which can be synergic with CSF1R inhibition in cancer treatment.

Li et al. characterize overlapping and divergent metabolic requirements of human and murine NK cells in response to activation, with a focus on serine metabolism

Transcriptome-scale maps of RNA secondary structure ensembles in living cells detect candidate RNA structural switches.

Chen et al. show that PEX39 cooperates with PEX7 in the peroxisomal import of proteins containing a PTS2 site and uncover an (R/K)PWE motif in PEX39 and PEX13 that binds to PEX7 and facilitates the import of PTS2-containing proteins.

Cells must coordinate cell division with genome replication. Here, the authors combine rapid protein depletion, clinical CDK4/6 inhibitors, and genome-wide EdU sequencing to reveal that the CDK4/6-RB axis ensures timely loading of DNA replication factors in G1 phase in human cells.

Using metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma mouse models, an ATP citrate lyase inhibitor reduces tumour burden and enhances efficacy of current standards of care.

Nagano et al. identify the third mitotic cohesin complex, STAG3–cohesin, which, with its unique biophysical properties, weakens insulation and rewires regulatory interactions of spermatogonial stem cells, shaping the male germline nucleome.

Engineered pyroptotic vesicles formed during tumour cell pyroptosis and engineered as personalized tumour vaccines can activate a robust antitumour immune response for post-surgical tumour recurrence inhibition.

How mitochondria positioning dynamically adapts to changes in cell shape is poorly understood. Here, Bradbury et al. show that cell-size-dependent trafficking of TRAK2 mRNA underpins the cell-size-scaling of mitochondria distribution and activity.

PARP inhibitor treatment triggers histone release from the chromatin in cancer cells; consequently, targeting the histone chaperone NASP renders cells vulnerable to PARP inhibition.

How changes in species’ native occupancy over time relate to global naturalization success remains unclear. Here, the authors show that species with both high occupancy decades ago and increasing native occupancy ever since are more likely to become naturalized elsewhere.

In mammals, the enzyme TGDS produces UDP-4-keto-6-deoxyglucose, which binds to the catalytic pocket of UDP-xylose synthase, thereby regenerating the essential NAD⁺ cofactor of UDP-xylose synthase in conditions of low NAD⁺.

LaFleur, Milling et al. perform an in vivo CRISPR screen of CD8⁺ T cells responding to tumors. They identify the E3 ubiquitin ligase STUB1 as a potent negative regulator of CD8⁺ T cell responses in tumors.

Wilms tumours are the most common malignant kidney tumour type in children, and their low mutational burden has impeded the development of targeted therapies. Here, the authors perform a proteogenomic characterisation of Wilms tumours, revealing molecular subtypes with different clinical features and identifying EHMT2 as a potential prognostic marker and therapeutic target.

By selectively isolating and sequencing the rare RNA transcripts containing C9orf72 repeat expansion from ALS–FTD neurons, the authors uncover an alternative splicing mechanism that explains the retention of this intron segment in a translated mRNA.

Intratumoral hypoxia promotes cancer progression. Here, authors show that hypoxia upregulates RNA Polymerase I activity and ribosome biogenesis in breast cancer cells and targeting RNA Polymerase I with BMH-21 reduces tumor growth and metastasis in murine models.

Mutation of positively charged binding sites on the eastern equine encephalitis virus (EEEV) E2 glycoprotein affects both heparan sulfate and protein receptor binding, identifying an unexpected linkage between engagement of these two receptor types.

The management of ulcerative colitis (UC) remains challenging due to the complexity of its etiology. Here, the authors establish that argininosuccinate synthetase 1 (ASS1) and its metabolite arginine are pivotal inducers of UC, through the triggering of mTOR and iNOS activation, and the induction of gut microbiota dysbiosis by metabolomics and proteomics. Inhibition of ASS1 by C-01 provides a viable strategy for the treatment of UC.

The N-acyl-cyclolysine system regulates the expression of co-localized operons encoding diverse secreted molecules in Bacteroidota.

Lee et al. show that the circadian clock protein REV-ERBα controls brain NAD⁺ levels by regulating the NAD⁺-consuming enzyme CD38. Global or astrocytic REV-ERBα deletion or pharmacologic REV-ERB inhibition protects against tau pathology in mice.

Lineage switching (LS) facilitates acute myeloid leukemia (AML) escaping CD19 targeted immunotherapy, but the underlying mechanism are not well understood. The authors here analyze patients’ single-cell mass cytometry and single-cell transcriptomics data, and identify an LS AML with the MDSC-like phenotype which is associated with LS in AML with KMT2A rearrangement.

According to Elton’s biotic resistance hypothesis, species-rich communities are more resistant to plant invasion. Guo et al. examine a dataset of over 12,000 vegetation plots and report that the influence of resident community richness and relatedness on invasion resistance varies in direction and magnitude along the introduction–naturalization–invasion continuum.

Protein-mediated transport is implicated in trafficking fatty acids at contact sites of lipid droplets and mitochondria. Here, the authors use proteomics to catalogue the proteins at this contact site and report a mechanism of fatty acid transfer that regulates fatty acid oxidation and lipid homeostasis.

PARP inhibitors are effective in cancer patients with BRCA1 mutations but whether this can extend to BRCA1 wildtype patients by targeting BRCA1 transcriptional regulation is unclear. Here, in preclinical models of pancreatic cancer, the authors identify OFD1 as a transcriptional regulator of BRCA1 via the DREAM complex and as a potential therapeutic target in combination with PARP inhibition.

Design of cysteine-targeting analogs of a reversible SETDB1 triple Tudor domain (3TD) ligand, UNC6535, led to UNC10013, a potent covalent ligand with high selectivity. UNC10013 demonstrated allosteric inhibition of SETDB1-mediated Akt methylation in cells, a promising approach to SETDB1 therapeutics.

Here they show that HDAC6 inhibition regulates fumarate hydratase (FH), disrupts mitochondria, increases fumarate, and causes cancer cell death. This suggests that HDAC6 inhibition could be a strategy to target tumour metabolism indirectly.

In a model of acute kidney injury the authors show that Pannexin1 can mediate a leak of Calcium from the endoplasmic reticulum leading to mitochondrial calcium overload and pro-senescence signals, and ultimately driving fibrosis and kidney disease progression

Two polypeptides synthesized by common bacterial strains in human gut microbiota lower body fat and blood glucose and increase bone density, improving the metabolism of rodents.

17β-oestradiol establishes an anti-ferroptotic state in female kidney tubules.

Deltex E3s modify ADP-ribosylated targets with ubiquitin, creating a hybrid modification whose readers remains unknown. Here, the authors synthesise a non-hydrolysable probe that mimics the modification and identify RNF114 as an interactor. RNF114 binds tightly to this modification and further elongates it with a K11-linked ubiquitin chain.

Carbohydrate esterases alter polysaccharides by removing ester groups. Here, the authors resolved crystal structures of two CE20 enzymes and discovered a novel, water-mediated catalytic triad essential for activity, offering insights into enzyme function and mechanism.

LYMTACs are heterobifunctional small molecules that take advantage of lysosomal membrane proteins to degrade membrane targets via relocalization and lysosomal degradation, offering a modular approach to drug otherwise intractable membrane proteins.

Hutchinson-Gilford Progeria Syndrome is characterized by premature aging with cardiovascular disease being the main cause of death. Here the authors show that inhibition of the NAT10 enzyme enhances cardiac function and fitness, and reduces age-related phenotypes in a mouse model of premature aging.

Using RFdiffusion, a general method for targeting intrinsically disordered proteins and regions for protein design has been developed.

In this study, Leventhal et al. integrate multi-omic data from human and Drosophila models of Alzheimer’s disease to define regulators of age-associated neurodegeneration in Alzheimer’s disease and the pathways through which they act.

In this work, authors study a molecular signature in STING protein that is critical for distinguishing activation from inhibition and demonstrates therapeutic potential in correcting STING-related mutations in autoimmune conditions like STING-Associated Vasculopathy with onset in Infancy (SAVI).

The network of proteins secreted for interorgan communication is poorly understood. Here, the authors develop a method, based on protein labeling, to study cell-specific secretomes and interorgan protein trafficking, and demonstrate their approach in Drosophila and mouse models.

Floss-based vaccination exploits the leaky junctional epithelium of the gingival sulcus to deliver different types of vaccine, inducing robust mucosal and systemic immunity and providing protection against respiratory infection.

Glutarate rewires cell metabolism through conjugation to proteins or fatty acids, but how glutarylation is regulated is unclear. ABHD11 was identified as a lipoyl-deglutarylase to maintain the TCA cycle and mitochondrial metabolism.

Exome sequencing of 851 trios from more than 2,500 individuals finds 187 genes with de novo mutations that contribute to meningomyelocele (spina bifida) and highlights critical pathways required for neural tube closure.

The authors report that acetylation of cytochrome c on K39 acts as a molecular switch in ischemic skeletal muscle, but not other tissues, to increase respiration and prevent apoptosis. This gives skeletal muscle robust resilience to ischemia and ischemia-reperfusion injury.