Cadar et al. show that the transcription factor Dorsal forms clusters at genes carrying many binding sites in living fly embryos. Losing these clusters is lethal, yet they do not switch genes on; they merely boost output from already-active genes, challenging prevailing views of how condensates control transcription.

Le Rest et al. identify ZC3H18 as the long-sought molecular link between the cap-binding complex (CBC) and first intron splicing. ZC3H18 recruits early splicing factors through interactions that are mutually exclusive with RNA decay factor binding, implying how cap-bound nascent transcripts are directed toward productive splicing rather than degradation.

Sommerova et al. show that ataxia telangiectasia-mutated (ATM) protects replicating cells by restraining pathological bypass of endogenous oxidative base lesions through PRIMPOL-mediated repriming. When ATM is lost, post-replicative adducted ssDNA gaps accumulate, creating dependence on homologous recombination for repair and driving PARP hyperactivation and PARP inhibitor sensitivity.

Qin et al. present unZipro, a geometric deep learning framework that adapts general protein design models to specific protein families. By leveraging meta-learning, unZipro efficiently navigates family-specific fitness landscapes, enabling rapid protein evolution across gene editing, luciferase reporting, transcriptional regulation, and antiviral resistance with minimal experimental screening.

Brown et al. demonstrate that full-length but not truncated CaMKII monomers can bind GluN2B. The truncated monomers could still induce synaptic potentiation but only after making them artificially autonomous in a phosphatase-insensitive manner, which is normally achieved by GluN2B binding.

Akbari et al. investigated the mechanisms of linker histone H1.0 loading onto nucleosomes. H1.0 directly binds nucleosomes and DNA, while DNA-bound H1.0 is mobile but does not load onto nucleosomes. Linker histone chaperones facilitate H1.0 loading through enhancing nucleosome binding, increasing H1.0 mobility, and enabling H1.0 loading through DNA sliding.

In this issue of Molecular Cell, Koo et al. describe how the yeast Rad55-Rad57-SHU complex dynamically nucleates Rad51 filaments on DNA. Functional coupling between Rad55-Rad57 and Rad51 on ssDNA seeds filament growth, whilst ATP hydrolysis promotes complex turnover.

In a recent issue of Science, Gao et al. discover a link between pattern-triggered immunity (PTI) initiated by plant cell surface receptors and effector-triggered immunity (ETI) initiated upon detection of pathogen effectors by intracellular nucleotide-binding leucine-rich repeat (NLR) immune receptors. PTI activates alternative splicing that results in mRNAs for the potato NLR Rpi-vnt1.1 that lack a repressive N-terminal prodomain.

Yatskevich et al. show that HUWE1 amplifies existing ubiquitin tags through chain elongation and branching. A cryo-EM structure reveals multivalent HUWE1-USP7 assembly and reciprocal regulation, while HAPSTR1 tunes substrate capture by engaging HUWE1 ubiquitin-binding motifs, defining a coordinated system for short-lived nuclear protein turnover.

Proteotoxic stress challenges multiple organelles, but how plants coordinate proteasome capacity with organellar function remains unclear. Langin et al. reveal that endoplasmic reticulum (ER)-associat...

Proteins have been often assumed to recognize interaction partners one amino-acid residue at a time. Jiang et al. introduce a computational and experimental platform that systematically captures epistatic, non-linearities (multiple amino-acid residues acting synergistically) in protein interactions. They uncover super-binding peptides and molecular determinants of non-linear binding from combinatorial deep mutational scanning (CDMS) libraries.

The TRiC/CCT chaperonin governs the enzymatic activity of RNA polymerase II (RNAPII), as changes in their interaction alter the global production of RNAPII-associated RNA. The balance between TRiC/CCT binding classic protein substrates and RNAPII contributes to RNA homeostasis.

Weinmann et al. show that HP1α represses mouse chromocenters through a local, promoter-proximal barrier rather than phase separation. HP1α and H3K9me3 persist as chromatin decondenses and is transcribed, and super-resolution imaging reveals transcription and HP1α segregated into independently switchable nanodomains captured by a quantitative model.

Looking in bacteria, Gill and Kim et al. reveal that mRNA sequences hundreds of nucleotides from the start codon can act as potent repressors of gene expression through long-range base pairing to the ribosome binding site (RBS). These distal anti-RBS sequences block ribosome entry and promote mRNA degradation.

Nie et al. demonstrate that the IRAK1-snRNA axis promotes MRN complex condensate formation to enhance ATM activation and maintain genomic stability at transcriptionally active regions.

Kainth et al. show that WDR5, a subunit of the MLL1 histone methyltransferase complex, binds RNA broadly rather than through specific sequences or motifs as proposed. This promiscuous binding competes with MLL1 complex formation to inhibit histone methylation, suggesting that local RNA abundance can feed back to tune chromatin modification activity.

López-Perrote et al. combine structural biology, single-molecule imaging, biochemistry, and cell biology to reveal how the lncRNA CONCR uses a conserved 3′ structural domain to recruit and activate DDX11. Their work demonstrates that RNA architecture, rather than sequence, underlies lncRNA control of DNA replication and genome stability.

Transcription factors (TFs) differ in their ability to interact with nucleosomes, and most TFs need other TFs to locate their motifs in the human genome. Here, Xiao et al. show that two ELF2 proteins are able to unwind DNA from nucleosomes and access all of their motifs in the genome.

Guan et al. show that bacteria use protein homologs with different material properties to regulate biomolecular condensates. By tuning the abundance of these proteins in heterotypic assemblies, bacteria balance condensate dynamics and stability, thereby maintaining fitness during stress.

Wang et al. introduce HoTs, self-blinking DNA probes for live-cell super-resolution chromatin imaging. Compatible with both STORM and MINFLUX microscopy, HoTs capture chromatin organization across live cells, animal tissues, and clinical tumor samples, opening new opportunities for studying genome architecture in health and disease.

Gene expression in human cells is programatically controlled for normal growth, development, and responses to the environment. Beyond known cyclin-dependent kinases, other overlooked kinases and factors may play indispensable roles in regulating transcription. Future molecular studies defining these regulators will improve knowledge and provide new treatment opportunities for diseases.

Frater et al. show an essential role of mammalian FACT in coordinating replisome and RNA polymerase progression through chromatin with histone recycling to maintain histone modifications. They further demonstrate that losing nucleosome organization can dynamically regulate chromatin compartmentalization.

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.

Schargel et al. engineer TnpB-family proteins into minimal de novo RNA-guided transposition systems. Nuclease-deficient TnpB-family proteins enable three-component DNA integration with high efficiency, target-site immunity, orientation control, and programmable insertion into the bacterial chromosome. In parallel, mutations to the TniQ-TnsC interface in wild-type V-K CAST attenuate off-site transposition.

Kaposin is an abundant viral RNA produced by the virus, Kaposi’s sarcoma-associated herpesvirus (KSHV). Kleer et al. reveal that kaposin drives nuclear speckle formation adjacent to the viral genome, enhancing viral gene expression. Kaposin is necessary and sufficient for this effect, which requires repeats regions within the RNA.

Contreras-Pérez et al. address the puzzling role of cohesin on transcription by focusing on the mitotic exit, when cohesin firstly contact chromatin. Combining in vivo labeling, cell-cycle synchronization, and acute protein depletion, authors demonstrate the preservation of cohesin across mitosis and its fundamental role on transcription reactivation of tissue-related genes.

Xiang et al. identify ECAS, a chromatin-associated complex that couples an elongation module (AFF4-ELL2-EAF1) to a spliceosome-associated intron binding complex. AQR/XAB2-dependent ECAS functions drive productive RNA Pol II elongation, nascent RNA capping, and co-transcriptional splicing and are required for leukemia initiation, maintenance, and leukemia stem cell function in MLL-rearranged leukemia.

Gao et al. reveal that the clinically used drug 5-azacytidine (5-azaC) induces transcriptional repression through RNA 5-methylcytosine (m5C) depletion, rather than acting solely as a DNA hypomethylating agent. Loss of m5C disrupts both MBD6-mediated H2AK119ub removal and SRSF2-mediated H3K27ac deposition, triggering leukemia cell death via cell-cycle disruption and defective DNA repair.

The TRiC/CCT chaperonin governs the enzymatic activity of RNA polymerase II (RNAPII), as changes in their interaction alter the global production of RNAPII-associated RNA. The balance between TRiC/CCT binding classic protein substrates and RNAPII contributes to RNA homeostasis.

Looking in bacteria, Gill and Kim et al. reveal that mRNA sequences hundreds of nucleotides from the start codon can act as potent repressors of gene expression through long-range base pairing to the ribosome binding site (RBS). These distal anti-RBS sequences block ribosome entry and promote mRNA degradation.

Weinmann et al. show that HP1α represses mouse chromocenters through a local, promoter-proximal barrier rather than phase separation. HP1α and H3K9me3 persist as chromatin decondenses and is transcribed, and super-resolution imaging reveals transcription and HP1α segregated into independently switchable nanodomains captured by a quantitative model.

Adaptation to thermal stress requires cells to interpret temperature changes in molecular terms to initiate biochemical responses. In this issue of Molecular Cell, Ueno et al. uncover a protein phosphorylation circuit as a potential thermosensor, linking stress to changes in global mRNA splicing.

Nuclear pore complex assembly is an intricate process occurring in the double bilayer of the nuclear envelope. In this issue of Molecular Cell, Fischer et al. Maslennikova et al. and Wang et al. integrate genetic analysis across model organisms with functional studies and molecular simulations to better understand a key step—membrane fusion.

Therapeutic mRNAs rely heavily on the incorporation of the RNA modification N1- methylpseudouridine for their efficacy. Schiffers et al. present N4-acetylcytidine as a robust alternative that further enhances protein production, broadening the chemical repertoire available for designing the next generation of mRNA medicines.

Zaatra, Philippos, et al. demonstrate that loss of the tumor suppressor p53 causes excessive transcription that depletes nucleotide pools required for DNA replication. The nucleotide shortage induces replication stress, genomic instability, and chromothripsis. These findings uncover a mechanism by which p53 safeguards genome integrity by restraining transcription and preserving nucleotide homeostasis.

Betts et al. investigate how the viral 2A protein controls programmed −1 ribosomal frameshifting (PRF) in cardioviruses. Their findings reveal an unexpected protein-dependent riboswitch mechanism, providing new insights into how frameshifting can be conditionally activated and establishing the remodeling of structured RNA as a regulatory principle in viral translational control.

Chaturvedi et al. demonstrate that acidic transcription factors reposition genomic loci to nuclear speckles through both transcription-dependent and transcription-independent mechanisms, revealing that speckle association is actively established by cis-regulatory DNA elements and transcription factor properties rather than arising simply as a consequence of active gene expression.

Human splicing is noisy, with cryptic splicing at both high- and low-fidelity motifs, associated with features that probabilistically increase stochastic splice site usage. These findings reveal a distinct layer of noise in the regulation of gene expression.

Wang et al. reveal a metabolite-tRNA charging mechanism that links metabolic state directly to translational control. Intracellular lactate accumulation directly represses mRNA translation via lactate-tRNA charging mediated by AARS1, uncovering an intrinsic metabolic brake that aggressive tumors evade by exporting lactate and identifying a therapeutic vulnerability to suppress cancer cell fitness.

Jimenez-Moreno et al. reveal that ER-phagy receptors directly control cytosolic signaling events. Upon stimulation, cytoplasmic PRKAR1A condensates interact with FAM134B/C, forming inter-organellar contacts that bridge the ER and lysosomes into a localized hydrolytic hub. This hub drives the degradation of RhoA, coordinating morphology transitions during cancer cell invasion.

Braun et al. identify that the canonical host mRNA deadenylation complex and an RNA-binding specificity factor, TTP, post-transcriptionally control antiviral interferon mRNAs through targeted deadenylation. Loss of mRNA decay machinery leads to a potent block against SARS-CoV-2 infection and can prime cells for innate immune memory.

Boulanger et al. study the coordination between cis-regulatory elements by simultaneously measuring their chromatin accessibility on the same kilobase-long DNA molecules. They show that co-accessibility identifies functionally dependent enhancers and promoters that have coordinated activity across cell types.

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.

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.