In this issue of Molecular Cell, Nengroo et al. report that the tricarboxylic acid (TCA) cycle enzyme succinate dehydrogenase (SDH) is essential for de novo purine synthesis, revealing a previously unrecognized metabolic dependency in cancer that can be leveraged therapeutically.

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.

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.

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.

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.

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.

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.

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.

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.

Ly et al. demonstrate that alternative start codon selection generates distinct N-terminal isoforms from a single mRNA, influencing mitochondrial function, evolution, and rare diseases. They uncover mechanisms controlling alternative N-terminal isoform localization and show that disease alleles can selectively disrupt specific isoforms, terming these mutations as “isoform-selective alleles.”

Yuan et al. uncover how the bacterial defense system Eco8 detects and combats phage infection. Through structural and biochemical analyses, they show that phage ssDNA-binding proteins trigger Eco8 activation, conferring broad-spectrum immunity. This work highlights msDNA as both a structural component and a phage sensor in antiviral defense.

The cryo-EM structure of the retron Eco8 system reveals an autoinhibited 4:4:4 complex of RT, msDNA, and OLD nuclease. Phage SSB binding to msdDNA unleashes non-specific nuclease activity to restrict phage replication, establishing msDNA as a molecular switch for Eco8 activation.

Lauriola, Enriqué Steinberg, et al. report that RNF32, a ubiquitin ligase enriched in intestinal stem cells, links calcium levels to NF-κB signaling by activating the IKK complex. This study uncovers a calcium-dependent mechanism involved in responses to bacterial stimuli, revealing how intestinal cells integrate signaling cues to regulate intestinal homeostasis.

Ranawat et al. show the cryo-EM structures of Asgard archaeal chromatin assemblies, revealing that the histone HHoB assembles into both compact closed and extended open hypernucleosomes. The closed conformation is conserved across archaea, while the open conformation represents an Asgard-specific innovation.

Nengroo et al. show that succinate dehydrogenase (SDH) maintains purine synthesis. SDH inhibition elevates succinate, inducing SHMT2 succinylation that suppresses mitochondrial one-carbon flow and formate supply, thereby constraining purine assembly. Cancer cells compensate via purine salvage, and dual inhibition of SDH and salvage yields significant antiproliferative effects and suppresses tumor growth.

Zhao et al. engineer a eukaryotic Fanzor nuclease, SpuFz1 V4, to achieve efficient genome and base editing in mammalian cells and in vivo. Its ultracompact size allows single-AAV delivery, highlighting its promise as a next-generation therapeutic genome editing platform.

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.

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.

Le Bozec et al. show that DSBs in transcribed loci in human cells are relocated and tethered to the nuclear envelope in a manner that depends on PER2, a protein of the PERIOD complex involved in the circadian clock. This mechanism contributes to homologous recombination repair and counteracts translocation frequency.

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.

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.

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.

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.

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.