Duan et al. solved the structure of ATRX ATPase-nucleosome complex, uncovering three distinctive features that enable ATRX to remodel nucleosomes. These newly identified features are indispensable for protecting cells from G4 stress. The work provides a framework for interpreting both known and future mutations linked to ATRX-related disorders.

Interpretability must be a first-class design objective for the next generation of foundation models in molecular biology. In this perspective, Varma and Ideker examine the ways in which it can be built into a model, from biological priors to architecture, and provide a checklist for authors and reviewers.

Tsai et al. discover that ribosome composition is reprogrammed in response to intrinsic and external cellular perturbations, which supports ribosome remodeling as a conserved mechanism that enables adaptive protein synthesis during pathogen infection and cellular adaptation.

Dossin et al. report that BRCA1 and BRCA2 deficiencies create distinct adaptive states. They identify FANCM-RMI1/2 as an opposing determinant of cell fitness: essential in BRCA1-deficient cells but toxic in BRCA2-deficient cells, where it drives replication fork degradation. Disrupting FANCM-RMI1/2 restores genome stability and promotes PARPi resistance in BRCA2-deficient cells.

Porat et al. develop cell surface ATAC-See, discovering that mitochondrial DNA is a component of the mammalian cell surface. Cell surface DNA (csDNA) on primary human and murine B cells and monocytes is removed by the secreted nuclease DNASE1L3, and dysregulation of csDNA levels is associated with autoimmunity.

Suzawa and Qiu et al. identify “two-factor authorization” of post-transcriptional gene regulation by germline-specific RNA-binding proteins DND1 and NANOS3. As a complex, the two proteins with low (DND1) and no (NANOS3) sequence specificity select targets with a unique 3′ UTR to collaboratively repress expression of cell cycle and epigenetic regulators.

Ferman et al. demonstrate that epigenetic imbalance directly controls MYC oncogene amplification dynamics, which identifies possible biomarkers and therapeutic targets for aggressive tumors. When a cell-death checkpoint fails, the low MYC copy gains expand to high levels, which include circular and integrated events and associate with tumorigenesis.

Papers in Molecular Cell and Cell by Xue et al. and Tsukuda et al., respectively, reveal that DDIAS serves as an essential single-stranded DNA (ssDNA)-binding effector of the CIP2A-TOPBP1 complex that safeguards genome integrity by shielding post-replicative ssDNA lesions during mitosis, with implications for human cancer and neurodevelopment.

In this issue of Molecular Cell, Chu et al.1 describe that cancers with increased cyclin E-CDK2 activity suppress responses to immunotherapy through phosphorylation of BRD4, resulting in downregulation of interferon-stimulated genes. Their findings suggest approaches to enhance immunotherapy responses.

Glioma cells experience profound metabolic stress in hypoxic tumor regions, where mitochondrial respiration is constrained and redox balance becomes difficult to maintain. A recent study by Vettore and colleagues in Molecular Cell identifies nicotinamide nucleotide transhydrogenase as a key mitochondrial enzyme that connects NADH oxidation to NADPH production, thereby supporting proline synthesis and growth under hypoxia. This work highlights how distinct redox pools are coordinated in cancer cells and suggests that NNT-dependent metabolism may represent a vulnerability in hypoxic tumors.

In a recent Nature paper, Witus et al. show that endogenous purine nucleotides and thiopurine drugs act as molecular glues to block purine synthesis by tethering PPAT to its inhibitor NUDT5 via a pocket highlighted by plasticity and cooperative interactions.

Drake et al. show that RPA activates the deubiquitinase ZUP1 to edit branched ubiquitin chains on DNA-bound RPA. This remodeling enables p97/VCP-dependent extraction of RPA from single-stranded DNA, preventing pathological RPA trapping and preserving genome stability.

Naydenova, Mund, Yip, et al. investigate the innate immune sensor ZNFX1, an RNA helicase and E3 ubiquitin ligase. Cryo-EM structures reveal that ZNFX1 is an auto-inhibited RNA helicase that forms large helical assemblies. Both ZNFX1 assemblies and ubiquitin ligase activity regulate ZNFX1 stability. Disease-associated mutations disrupt catalytic activities of ZNFX1.

Complexome profiling integrated with single-particle cryo-EM reveals how conserved and lineage-specific mitochondrial proteins assemble into macromolecular complexes in the kinetoplastid protozoans Trypanosoma brucei and Leishmania tarentolae.

Mitochondrial proteome atlases of Trypanosoma brucei and Leishmania tarentolae reveal deep conservation alongside extensive lineage-specific innovation within Kinetoplastea. Comparative analyses across life-cycle stages uncover metabolic remodeling.

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.

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.

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.

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.

Chu et al. show that cyclin E-CDK2 has a cell-cycle-independent role in transcriptional regulation by phosphorylating BRD4 and controlling its chromatin occupancy. Cyclin E overexpression represses the expression of interferon-stimulated genes in cancer cells through BRD4 and promotes immunotherapy resistance, while inhibition of CDK2 activity enhances responses to immune checkpoint blockade.

Xue et al. identify DDIAS as an effector of the CIP2A-TOPBP1 complex. DDIAS is a single-stranded DNA-binding protein that promotes the repair of single-stranded DNA lesions during cell division. This activity is essential in cells lacking the BRCA1 or BRCA2 tumor suppressors or in cells lacking DNA polymerase ζ.

Vettore and Boufersaoui et al. show that glioma cells require efficient regeneration of mitochondrial NADPH through the enzyme nicotinamide nucleotide transhydrogenase (NNT) to adapt to metabolic and redox challenges in hypoxia. Glioma cells lacking sufficient NNT activity have strongly impaired growth in vitro and in vivo.

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.