Borne to be wild: ecDNA as a vehicle for oncogenic fusion In a recent Cell paper, Yi and Zhang et al. reveal that ecDNA serves as a platform for the generation of oncogenic fusion transcripts, particularly PVT1 5′ end-based fusions, which enhance oncogene expression and drive cancer progression beyond gene amplification alone.

Borne to be wild: ecDNA as a vehicle for oncogenic fusion

Glues that can STING: Lipids in innate immunity Phosphoinositides regulate cellular signaling. Tan et al. and Li et al. identify PtdIns(3,5)P₂ and cholesterol as key lipids that stabilize STING oligomers and enable TBK1 activation, explaining why STING must traffic from the ER to the Golgi to initiate immune signaling.

Glues that can STING: Lipids in innate immunity

FOXF1/2 establish a senescence-specific enhancer landscape to activate the pro-inflammatory senescence-associated secretory phenotype Etoh et al. identify that FOXF1/2 transcription factors define the enhancer landscape to establish the senescent transcriptome program. FOXF1/2 recruit the p300/CBP acetyltransferases and cooperate with AP-1 c-JUN to deposit H3K27 acetylation, increase chromatin accessibility, and shape de novo enhancers in pro-inflammatory SASP genes of senescent cells.

FOXF1/2 establish a senescence-specific enhancer landscape to activate the pro-inflammatory senescence-associated secretory phenotype

Mitochondrial translation elongation controls OXPHOS biogenesis by coordinating synthesis and folding of mitochondrially encoded proteins Xie et al. show that mitochondrial translation elongation rate influences OXPHOS biogenesis. In the filamentous fungus Neurospora crassa, MRM1 slows elongation speed independently of its methyltransferase activity by simultaneously binding mitoribosomes and mRNAs, thereby coordinating synthesis with folding and membrane insertion of mitochondrially encoded OXPHOS subunits.

Mitochondrial translation elongation controls OXPHOS biogenesis by coordinating synthesis and folding of mitochondrially encoded proteins

mTORC1 activity suppresses ferroptosis through a SCARB1-dependent HDL-tocopherol uptake pathway O’Loughlin et al. identify SCARB1 as an mTORC1-regulated ferroptosis suppressor. They demonstrate that mTORC1 activity promotes the expression of SCARB1 to facilitate the uptake of tocopherol-loaded high-density lipoproteins (HDL). Consequently, mTORC1 inhibition impairs the acquisition of these antioxidant defenses and renders cells dependent on GPX4 activity and sensitive to ferroptosis-inducing insults.

mTORC1 activity suppresses ferroptosis through a SCARB1-dependent HDL-tocopherol uptake pathway

Structural basis for TORC2 activation Zou et al., combining cryo-EM with structure predictions, report a high-resolution structure of TORC2 revealing previously unobserved flexible subunits and domains important for the regulation of kinase activity. Phenotypic analyses of structure-bespoke mutants proffer a model of allosteric activation by plasma membrane signaling lipids.

Structural basis for TORC2 activation

Multivalent 28S rRNA expansion segments enable reconstitution of multilayered nucleolar architecture Wei et al. demonstrate that 28S rRNA expansion segments are critical for multilayered nucleolar architecture formation through multivalent RNA-RNA interactions. Expansion segments from tripartite-nucleolus species confer enhanced multivalency of 28S rRNA, and transferring these segments across species is sufficient to induce nucleolar-like layered structures in vitro.

Multivalent 28S rRNA expansion segments enable reconstitution of multilayered nucleolar architecture

Metabolic profiling reveals pyrimidine synthesis enzyme CAD as a central carbon metabolism signaling node in cancer cell proliferation Qin et al. show that the pyrimidine synthesis enzyme CAD reprograms central carbon metabolism by deamidating G6PD and PHGDH, thereby fueling the formation of tumors, including hepatocarcinoma. Targeting the unconventional enzyme activity of CAD offers a promising therapeutic strategy.

Metabolic profiling reveals pyrimidine synthesis enzyme CAD as a central carbon metabolism signaling node in cancer cell proliferation

Species-specific cleavage of the autophagy adaptor p62 dictates responses to TNF Nössing et al. find that TNF signaling triggers caspase-8-mediated cleavage of the autophagy adaptor p62/SQSTM1, generating a truncated form of the protein that stabilizes RIPK1-dependent complex-IIb, promoting cell death. Mice cannot generate cleaved p62 due to a sequence divergence; knockin of the p62 cleavage site enhances inflammatory responses in vivo.

Species-specific cleavage of the autophagy adaptor p62 dictates responses to TNF

BRCA2-dependent maturation of nascent strands during DNA replication Milano et al. identify a role for BRCA2 in nascent strand maturation during DNA replication in the presence of PARP inhibitor.

BRCA2-dependent maturation of nascent strands during DNA replication

2′-O-Methylation maintains ribosome structural and translation integrity By examining the translational properties and high-resolution structural features of yeast ribosomes lacking snoRNP-directed rRNA 2′-O-methylation, Zhao et al. demonstrated that 2′-O-methylation is essential for maintaining translation fidelity, efficiency, and ribosome structural integrity.

2′-O-Methylation maintains ribosome structural and translation integrity

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LENG8 mediates RNA nuclear retention and degradation in eukaryotes Tian et al. identify LENG8 as a conserved RNA quality-control factor that prevents nuclear export of misprocessed mRNAs and noncoding RNAs. This study provides fundamental insight into how the surveillance machinery monitors RNA processing status to determine nuclear retention, degradation, or export.

LENG8 mediates RNA nuclear retention and degradation in eukaryotes

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H2AK119ub1-MLL2 counteraction underlies heritable H3K27me3 formation in oocytes Mei et al. reveal that the Polycomb mark H2AK119ub1 maintains gene silencing in mouse oocytes by opposing MLL2 activity, enabling the establishment of heritable H3K27me3. They uncover how the balance between repressive and activating chromatin mechanisms shapes the maternal epigenome.

Online Now: H2AK119ub1-MLL2 counteraction underlies heritable H3K27me3 formation in oocytes Online now:

Condition-dependent amorphous protein agglomerates control cytoplasmic rheology Losa et al. show that nutrient-dependent changes in E. coli cytoplasmic rheology arise from amorphous agglomerates formed by self-association of amino acid metabolic enzymes. These agglomerates slow down macromolecular diffusion and increase cytoplasmic elasticity, revealing metabolic remodeling as a regulator of intracellular transport and organization.

Online Now: Condition-dependent amorphous protein agglomerates control cytoplasmic rheology Online now:

Multivalent 28S rRNA expansion segments enable reconstitution of multilayered nucleolar architecture Wei et al. demonstrate that 28S rRNA expansion segments are critical for multilayered nucleolar architecture formation through multivalent RNA-RNA interactions. Expansion segments from tripartite-nucleolus species confer enhanced multivalency of 28S rRNA, and transferring these segments across species is sufficient to induce nucleolar-like layered structures in vitro.

Online Now: Multivalent 28S rRNA expansion segments enable reconstitution of multilayered nucleolar architecture Online now:

Metabolic profiling reveals pyrimidine synthesis enzyme CAD as a central carbon metabolism signaling node in cancer cell proliferation Qin et al. show that the pyrimidine synthesis enzyme CAD reprograms central carbon metabolism by deamidating G6PD and PHGDH, thereby fueling the formation of tumors, including hepatocarcinoma. Targeting the unconventional enzyme activity of CAD offers a promising therapeutic strategy.

Online Now: Metabolic profiling reveals pyrimidine synthesis enzyme CAD as a central carbon metabolism signaling node in cancer cell proliferation Online now:

Species-specific cleavage of the autophagy adaptor p62 dictates responses to TNF Nössing et al. find that TNF signaling triggers caspase-8-mediated cleavage of the autophagy adaptor p62/SQSTM1, generating a truncated form of the protein that stabilizes RIPK1-dependent complex-IIb, promoting cell death. Mice cannot generate cleaved p62 due to a sequence divergence; knockin of the p62 cleavage site enhances inflammatory responses in vivo.

Online Now: Species-specific cleavage of the autophagy adaptor p62 dictates responses to TNF Online now:

BRCA2-dependent maturation of nascent strands during DNA replication Milano et al. identify a role for BRCA2 in nascent strand maturation during DNA replication in the presence of PARP inhibitor.

Online Now: BRCA2-dependent maturation of nascent strands during DNA replication Online now:

Hijacking by sequestration: An hCMV lncRNA reshapes the host transcriptome During hCMV infection, the highly abundant viral lncRNA RNA2.7 reshapes host gene expression by sequestering RNA-binding proteins, stabilizing host mRNAs, and enforcing G1 arrest. In this issue, Fisher et al. explore how this RNA-driven strategy optimizes the cellular environment for viral replication.

Hijacking by sequestration: An hCMV lncRNA reshapes the host transcriptome

A splicing factor’s unexpected detour to the mitochondrial surface In this issue of Molecular Cell, Garcia et al. reveal an unexpected role for the splicing factor U2AF in repressing translation and influencing the localization of nuclear-encoded mitochondrial mRNAs to the outer mitochondrial membrane.

A splicing factor’s unexpected detour to the mitochondrial surface

Precision from broad strokes: How the non-specific interactions of metabolites and macromolecules can regulate biology In a recent article in Nature, Zabala-Letona et al. propose that polyamines—small, positively charged metabolites—regulate RNA splicing by electrostatically shielding acidic sites on spliceosome proteins from kinase-mediated phosphorylation. This work adds to a growing body of evidence suggesting that metabolites can regulate cell biology through non-specific macromolecular interactions.

Precision from broad strokes: How the non-specific interactions of metabolites and macromolecules can regulate biology

The HIF-2 transcription factor mediates resistance to ferroptosis in pancreatic cancer Hubbi et al. reveal that hypoxia and pancreatic tumor interstitial fluid cooperate to suppress ferroptosis in pancreatic cancer through HIF-2 activity. By transcriptionally regulating glutathione metabolism and mitochondrial function, HIF-2 enables tumor survival in metabolically hostile environments, defining a tissue-specific role in pancreatic ductal adenocarcinoma.

The HIF-2 transcription factor mediates resistance to ferroptosis in pancreatic cancer

U2AF regulates the translation and localization of nuclear-encoded mitochondrial mRNAs Garcia et al. identify a non-canonical function of the splicing factor U2AF1 in translation and localization of nuclear-encoded mitochondrial RNAs. An oncogenic missense mutation leads to pervasive changes in the mitochondria proteome and multi-faceted mitochondrial dysfunction. Similar phenotypes are observed in primary hematopoietic stem cells from patients with myelodysplastic syndromes.

U2AF regulates the translation and localization of nuclear-encoded mitochondrial mRNAs

Chaperonin TRiC bridges radial spokes for folding locally translated proteins to sustain mammalian sperm flagellar motility Meng et al. identify the RS1-RS2 barrel (RRB) in mammalian sperm flagella as a unique TRiC/CCT chaperonin. In situ structures, local translation evidence, cross-linking MS, and inhibitor assays support that RRB-TRiC folds locally translated axonemal proteins to sustain prolonged motility for internal fertilization.

Chaperonin TRiC bridges radial spokes for folding locally translated proteins to sustain mammalian sperm flagellar motility

Transient residence of the repulsive client Shutdown in Yb bodies plays a critical role in Piwi-piRISC biogenesis and maintaining fertility Hirakata et al. reveal that Shutdown rapidly returns from Yb bodies to the cytosol through its repulsive N-terminal property. This dynamic release enables piRNA maturation and safeguards fertility, providing new insight into the mechanisms governing client protein exit from biomolecular condensates.

Transient residence of the repulsive client Shutdown in Yb bodies plays a critical role in Piwi-piRISC biogenesis and maintaining fertility

Mechanosensory channels mediate ER Ca2+ transients to trigger assembly of autophagosome initiation sites for degradation of ER subdomains Ma et al. show that stress-induced, high-luminal Ca2+ ER sheets are selectively degraded by autophagy (ER-phagy), which requires the concerted actions of FAM134B and lipidated LC3. The ER-localized channels PIEZO1 and TRPV1 mediate Ca2+ release from these ER subdomains, triggering the formation of FIP200 puncta to initiate autophagosome assembly.

Mechanosensory channels mediate ER Ca2+ transients to trigger assembly of autophagosome initiation sites for degradation of ER subdomains

An interactome-based framework for DDB1- and CUL4-associated factor prioritization in targeted protein degradation Yamanaka et al. map proximity-based interaction networks of the human DDB1- and CUL4-associated factor (DCAF) family. By integrating proteomics with measures of Cullin4-really interesting new gene (RING) ubiquitin ligase (CRL4) complex formation and activity, they define functional classes of DCAFs, identify candidate substrates, and prioritize ligases with high potential for targeted protein degradation.

An interactome-based framework for DDB1- and CUL4-associated factor prioritization in targeted protein degradation

The Erlin1/2 complex is a dynamic scaffold for membrane microdomain assembly on the endoplasmic reticulum Yan et al. reveal the structure of the ER-resident Erlin1/2 complex, showing how it assembles into a cage-like architecture that organizes functional membrane microdomains on the ER membrane and regulates cargo protein accessibility. These findings provide a structural framework for understanding Erlin-mediated processes on the ER membrane.

The Erlin1/2 complex is a dynamic scaffold for membrane microdomain assembly on the endoplasmic reticulum