Molecular Cell

Timing of transcription controls the selective translation of newly synthesized mRNAs during acute environmental stress Under stress, cells adapt their gene expression programs through changes in transcription and translation. It is unclear how cells determine which mRNAs are translated or repressed. Zedan et al. show that the timing of mRNA production alone determines the selectivity of translation, thereby coupling the processes of transcription and translation.

Timing of transcription controls the selective translation of newly synthesized mRNAs during acute environmental stress

Transcriptome-wide mRNP condensation precedes stress granule formation and excludes new mRNAs Glauninger, Bard, Wong Hickernell, et al. reveal that stress causes transcriptome-wide mRNP condensation, largely independent of length and often without stress granule formation, but newly synthesized mRNAs escape this sequestration, enabling their selective translation. Translation initiation inhibition causes condensation of mRNA, and these condensates are present even in unstressed cells.

Transcriptome-wide mRNP condensation precedes stress granule formation and excludes new mRNAs

Recycling of ribosomes at stop codons drives the rate of translation and the transition from proliferation to RESt Ribosome recycling’s role in translational regulation remains unclear. Miluzio, Scagliola, et al. show that blocking eIF6 phosphorylation by environmental stressors delays ribosome recycling at stop codons, leading to translational reprogramming and establishing RESt. RESt is reversible, characterized by metabolic remodeling, low translation, reduced reinitiation, and NF-κB pathway activation.

Recycling of ribosomes at stop codons drives the rate of translation and the transition from proliferation to RESt

UMP functions as an endogenous regulator of NR4A1 to control gastric cancer progression Cai et al. revealed a biosynthesis-independent function of UMP, that is, acting as an endogenous regulator of NR4A1 to control gastric tumor growth and progression. The unique function of NR4A1 may offer an effective therapeutic strategy for overcoming the limitation of DHODH inhibitor monotherapy in cancer.

UMP functions as an endogenous regulator of NR4A1 to control gastric cancer progression

Deubiquitinases cleave ubiquitin-fused ribosomal proteins and physically counteract their targeting to the UFD pathway Patchett et al. describe how the processing of ubiquitin-fused human ribosomal proteins can be regulated by both ubiquitin E3 ligases and DUBs to ensure proper ribosome function. Their findings show that the UFD pathway is critical for regulating the stability of ubiquitin-fused ribosomal proteins.

Deubiquitinases cleave ubiquitin-fused ribosomal proteins and physically counteract their targeting to the UFD pathway

HSP90 buffers deleterious genetic variations in BRCA1 Gracia et al. show that HSP90 buffers BRCA1 mutations by stabilizing the encoded mutant proteins, promoting PARP inhibitor resistance. Low-level HSP90 inhibition selectively hypersensitizes HSP90-buffered BRCA1 mutant cancer cells to PARP inhibition. Carriers of HSP90-buffered BRCA1 mutations develop cancer roughly 10 years later than those with non-buffered mutations.

HSP90 buffers deleterious genetic variations in BRCA1

Structure of the transcriptional co-activator SAGA complex, including the histone acetyltransferase module Mattoo et al. determined the HAT module structure within the SAGA complex using cryo-electron microscopy. This provides insights into histone acetylation and the overall architecture of the SAGA complex. They identified two SAGA core subunits involved in anchoring the HAT module, enhancing the understanding of the RNA polymerase II chromatin transcription mechanism.

Structure of the transcriptional co-activator SAGA complex, including the histone acetyltransferase module

High-throughput capture of actively transcribed region-interacting sequences reveals an intricate promoter-centered regulatory network Li et al. developed Hi-Coatis, an antibody- and probe-free method that employs Klenow polymerase to capture actively transcribed regions and their interaction loci. This approach simultaneously detects the activity of RNA polymerases I, II, and III and further reveals that repetitive elements exert regulatory functions in gene expression.

High-throughput capture of actively transcribed region-interacting sequences reveals an intricate promoter-centered regulatory network

Metabolic environment-driven remodeling of mitochondrial ribosomes regulates translation and biogenesis Zheng et al. demonstrate that mitochondria remodel the structure and composition of mitochondrial ribosomes in response to metabolic state. This structural “gear-switching” mechanism fine-tunes mitochondrial translation and biogenesis, compensating for the absence of dedicated signaling pathways within mitochondria.

Metabolic environment-driven remodeling of mitochondrial ribosomes regulates translation and biogenesis

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The landscape of regulated cell death: It’s all downhill from here The regulated cell death pathways apoptosis, pyroptosis, and necroptosis are connected on multiple levels. To provide a novel and intuitive conceptual framework of the collaborative and complex nature of this interplay, we visualize cell death commitment as a landscape model, on which a cell can “roll” downhill from life toward death.

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The Ppl protein senses 3′-hydroxyl DNA overhangs and NTP depletion to halt phage infection Xu et al. reveal that the Ppl defense system protects bacteria from phages by acting as a “double-check” security system. It requires two simultaneous phage-induced stresses to activate, a sophisticated mechanism that ensures effective immunity while preventing premature abortive infection.

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NAT10 promotes cancer metastasis by modulating p300/CBP activity through chromatin-associated tRNA Amin et al. demonstrate that the RNA acetyltransferase NAT10 regulates p300/CBP activity through acetylation of chromatin-associated tRNAs. Loss of NAT10 disrupts enhancer-mediated gene regulation and immune cell recruitment, revealing a link between RNA acetylation, chromatin organization, and tumor-immune interactions in metastatic progression.

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Rate-limiting enzymes in nucleotide metabolism synchronize nucleotide biosynthesis and chromatin formation Srivastava et al. show that the phosphoribosyl pyrophosphate synthetase (PRPS) complex, beyond its essential role in nucleotide biosynthesis, also regulates histone deposition on chromatin. Their findings uncover a functional link between nucleotide metabolism and chromatin regulation, demonstrating how nucleotide production and histone supply are coupled during chromatin formation.

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In vivo proteomic labeling reveals diverse proteomes for therapeutic targets Wang et al. establish an in vivo proteomic labeling (IVPL) system combining the Btn-Ph-3F substrate with APEX2-EGFPf/f Cre crosses to map cell-type-specific proteomes in intact organs and trace patient-derived exosomal proteins. IVPL identifies LDHAL6A as a pro-metastatic driver and highlights its potential as a therapeutic target in TNBC.

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Attenuation of ATM signaling by ROS delays replicative senescence at physiological oxygen Stuart et al. find that senescence is due to ATM responding to short telomeres with insufficient TRF2. They show that cells cultured at 3% (versus 20%) oxygen have increased ROS which creates crosslinked ATM dimers that do not respond to DSBs. This explains the extended replicative lifespan at low oxygen.

Online Now: Attenuation of ATM signaling by ROS delays replicative senescence at physiological oxygen Online now:

Timing of transcription controls the selective translation of newly synthesized mRNAs during acute environmental stress Under stress, cells adapt their gene expression programs through changes in transcription and translation. It is unclear how cells determine which mRNAs are translated or repressed. Zedan et al. show that the timing of mRNA production alone determines the selectivity of translation, thereby coupling the processes of transcription and translation.

Online Now: Timing of transcription controls the selective translation of newly synthesized mRNAs during acute environmental stress Online now:

Transcriptome-wide mRNP condensation precedes stress granule formation and excludes new mRNAs Glauninger, Bard, Wong Hickernell, et al. reveal that stress causes transcriptome-wide mRNP condensation, largely independent of length and often without stress granule formation, but newly synthesized mRNAs escape this sequestration, enabling their selective translation. Translation initiation inhibition causes condensation of mRNA, and these condensates are present even in unstressed cells.

Online Now: Transcriptome-wide mRNP condensation precedes stress granule formation and excludes new mRNAs Online now:

Recycling of ribosomes at stop codons drives the rate of translation and the transition from proliferation to RESt Ribosome recycling’s role in translational regulation remains unclear. Miluzio, Scagliola, et al. show that blocking eIF6 phosphorylation by environmental stressors delays ribosome recycling at stop codons, leading to translational reprogramming and establishing RESt. RESt is reversible, characterized by metabolic remodeling, low translation, reduced reinitiation, and NF-κB pathway activation.

Online Now: Recycling of ribosomes at stop codons drives the rate of translation and the transition from proliferation to RESt Online now:

DNA bendability inside the nucleosome regulates INO80’s nucleosome positioning Shukla et al. find that the INO80 chromatin remodeler positions nucleosomes at specific genomic positions, including the 5′ end of genes. INO80 recognizes DNA shape rather than a unique DNA sequence. Nucleosome movement is blocked when INO80 encounters inflexible DNA inside the nucleosome, mediated by the DNA-rigidity-sensitive binding of its Arp5 subunit.

Online Now: DNA bendability inside the nucleosome regulates INO80’s nucleosome positioning Online now:

Let’s wrap things up: Open and closed hypernucleosomes in Asgard archaea Asgard archaea are widely considered the closest living relatives of eukaryotes. In this issue of Molecular Cell, Ranawat et al. report high-resolution structures of hypernucleosomes formed by the hodarchaeal HHoB histone, disclosing open and closed chromatin conformations.

Let’s wrap things up: Open and closed hypernucleosomes in Asgard archaea

Succinate puts the brakes on de novo purine synthesis

A new horizon unfolding for insulin signaling in health and disease Wang et al. use innovative computational methods to design polypeptides that bind to and activate the insulin receptor tyrosine kinase, revealing strategies to resolve the composite insulin signal into distinct components for therapeutic use.

A new horizon unfolding for insulin signaling in health and disease

Leveraging biochemical covariance to better understand biology In a recent Nature article, Xiao et al. report development of a metabolite-protein covariation architecture (MPCA) database from a diversity outbred mouse cohort that facilitates the deciphering of metabolite-protein relationships in liver and brown adipose tissue (BAT). Using these correlations, the authors describe a role for LRRC58 in controlling cysteine-taurine metabolism.

Leveraging biochemical covariance to better understand biology

Getting sticky: How nuclear speckles tune the condensation-prone proteome Recent work by Faraway et al. uncovers interstasis—a feedback mechanism whereby the stiffening of nuclear condensates caused by the accumulation of condensation-prone resident proteins entraps mRNAs encoding these proteins, thereby limiting their translation to restore proteome balance.

Getting sticky: How nuclear speckles tune the condensation-prone proteome

Debranching enzyme DBR1-mediated lariat RNA turnover requires ALBA proteins in Arabidopsis Ge et al. report that the conserved ALBA family proteins promote lariat RNA degradation by interacting with DBR1, the key factor for lariat RNA debranching. Moreover, the N-terminal ALBA domain mediates the interaction with DBR1 and enhances its debranching activity, while the C-terminal RGG/RG repeats facilitate DBR1’s accessibility to lariat RNAs. Intriguingly, cold stress inhibits lariat RNA degradation by reducing the ALBA-DBR1 interaction, which in turn leads to hypersensitivity to cold. These findings reveal a novel layer of regulation in lariat RNA turnover.

Debranching enzyme DBR1-mediated lariat RNA turnover requires ALBA proteins in Arabidopsis

Divergent proteome tolerance against gain and loss of chromosome arms Di et al. report distinct proteostasis mechanisms for gain- and loss-type single-arm aneuploidy. In gain-type, compensation is primarily driven by increased protein degradation. By contrast, proteins encoded on the lost chromosome arm show no significant change in degradation rates but significant relative upregulation of protein synthesis, maintaining protein complex stoichiometry.

Divergent proteome tolerance against gain and loss of chromosome arms

A role for human senataxin in contending with pausing and backtracking during transcript elongation Han et al. use biochemistry and acute depletion of senataxin to reveal a role in RNAPII transcript elongation via reversal of pausing and backtracking. By contrast, senataxin has little direct effect on transcription termination.

A role for human senataxin in contending with pausing and backtracking during transcript elongation

Monitoring the complexity and dynamics of mitochondrial translation Wakigawa et al. present advanced derivatives of mitochondrial ribosome profiling. By quantifying initiation, elongation, and ribosome collisions and by dissecting the impacts of tRNA anticodon-loop modifications and the initiation mechanism of internal translons, they uncover dynamic regulation of mammalian mitochondrial translation that ensures cellular energy production.

Monitoring the complexity and dynamics of mitochondrial translation

Megabase-scale loss of heterozygosity provoked by CRISPR-Cas9 DNA double-strand breaks Regan et al. report that Cas9 double-strand breaks (DSBs) induce loss of heterozygosity (LOH) spanning megabases, which is suppressed by both the non-homologous and microhomology-mediated end-joining pathways. Long-range LOH distal to the DSB often arises from chromosome truncations, but centromere-proximal LOH can also occur at megabase scales.

Megabase-scale loss of heterozygosity provoked by CRISPR-Cas9 DNA double-strand breaks