Molecular Cell

SLC25A45 is required for mitochondrial uptake of methylated amino acids and de novo carnitine biosynthesis Dias et al. discover that the orphan solute carrier protein, SLC25A45, enables mitochondrial import of methylated amino acids. SLC25A45-dependent mitochondrial uptake of trimethyllysine drives carnitine biosynthesis. Mutation near its C terminus impacts SLC25A45 proteostasis and associates with altered methylated amino acid levels in human plasma.

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Engineered hypercompact Fanzor-ωRNA system with enhanced genome editing activity 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.

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Mechanism of DNA entrapment by a loop-extruding Wadjet SMC motor Wadjet is an SMC-based prokaryotic defense system that eliminates plasmid DNA. Roisné-Hamelin et al. present structures capturing key steps of its DNA-loading mechanism. This work reveals how Wadjet topologically entraps DNA by SMC dimer rotation around DNA and defines the starting point of loop extrusion by the SMC motor.

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A fork in the road: PADI4 citrullinates p53 to control immune-related networks How does the p53 tumor suppressor choose which transcriptional targets to regulate? In this issue, Indeglia et al. reveal that PADI4 citrullinates p53, redirecting its binding to ETS sites, enhancing immune-related gene expression, and promoting tumor suppression.

A fork in the road: PADI4 citrullinates p53 to control immune-related networks

Spheres, worms, and packing problems in the nanoscale assembly of ALS-linked protein Matrin-3 Matrin-3 (MATR3) is an RNA-binding protein that forms higher-order assemblies and pathological inclusions associated with neurodegenerative diseases. In this issue of Molecular Cell, Sprunger et al. explore the assembly of MATR3 and find that it forms spherical and worm-like nanoscale assemblies distinct from condensates formed by macrophase separation.

Spheres, worms, and packing problems in the nanoscale assembly of ALS-linked protein Matrin-3

And now for something completely different in co-translational targeting In two recent papers in Cell, Zhu et al. and Luo et al. use selective ribosome profiling to identify the substrates and timing of co-translational protein targeting to mitochondria. The results suggest a mechanism that is very different from the classic ER signal-recognition-particle pathway.

And now for something completely different in co-translational targeting

A needed nomenclature for nucleosomes Keogh et al. propose a nomenclature to clearly and concisely describe the post-translational modifications, proteoforms, and nucleoforms that drive chromatin function. This communicates experimental nuance and how multiple attributes mediate function through specific molecular configurations. Such a framework is applicable to proteins and their complexes across biology.

A needed nomenclature for nucleosomes

PARP1 auto-modification promotes faithful Okazaki fragment processing and limits replication fork speed Using a separation-of-function mutant, Elsborg et al. explore the distinct roles of PARP1 auto-modification and trans-ADP-ribosylation. Auto-modification regulates DNA replication fork progression, prevents replication stress, and is required for PARP1 eviction from DNA-damage sites. Its loss is synthetic lethal with FEN1 inhibition, highlighting a key role in Okazaki fragment processing.

PARP1 auto-modification promotes faithful Okazaki fragment processing and limits replication fork speed

Targeted citrullination enables p53 binding to non-canonical sites Indeglia et al. describe a new post-translational modification that alters p53 function.

Targeted citrullination enables p53 binding to non-canonical sites

A network of P-body and Whi3 condensates adjusts cell fate decisions to cellular context Peskett et al. show that P-bodies and the Whi3 protein form distinct condensates as budding yeast cells age. Mixing of these condensates promotes senescence entry and primes cells to abort the pheromone response. This shows that single cells use combinations of biomolecular condensates to integrate information.

A network of P-body and Whi3 condensates adjusts cell fate decisions to cellular context

Lipid-regulated phosphorylation hierarchy of the T cell receptor tyrosine motifs Li et al. report the NMR structure of the membrane-bound cytoplasmic tail of CD3ζ, a key TCR signaling subunit. Its ITAMs show graded membrane insertion, leading to sequential phosphorylation. Under chronic antigen stimulation, partial ITAM phosphorylation in exhausted T cells implicates the contribution of altered TCR signaling in T cell dysfunction.

Lipid-regulated phosphorylation hierarchy of the T cell receptor tyrosine motifs

A Leishmania virulence factor harnesses an allosteric kinase switch to regulate its ubiquitin ligase activity Fokkens et al. identify a eukaryotic module combining kinase and ubiquitin ligase domains. This module is part of a Leishmania virulence factor, TKUL, that requires both enzymatic activities and employs HSP70 adaptors for substrate ubiquitylation. This activity is allosterically controlled by the kinase, enabling suppression of ubiquitylation by kinase inhibitors.

A Leishmania virulence factor harnesses an allosteric kinase switch to regulate its ubiquitin ligase activity

The nuclear pore complex connects energy sensing to transcriptional plasticity in longevity Zhou et al. identify an ancient role of the nucleoporin NUP50 in pro-longevity responses to nutrient stress, independent of its role in nuclear transport. The authors show that nutrient stress activates NUP50 post-translationally, rewiring metabolism and promoting longevity through its intrinsically disordered region, coupling energy sensing to protective transcriptional responses.

The nuclear pore complex connects energy sensing to transcriptional plasticity in longevity

Ubiquitin precursor with C-terminal extension promotes proteostasis and longevity Altin et al. identified CxUb, a C-terminally extended ubiquitin molecule dedicated to overcoming stress and present in all eukaryotic genomes. CxUb marks client proteins for efficient degradation by the proteasome, ensuring cellular quality control. CxUb function is critical specifically in stressed cells, safeguarding healthy ones and contributing to healthy aging.

Ubiquitin precursor with C-terminal extension promotes proteostasis and longevity

Rapid remodeling of NTP levels enables immediate translational adaptation to energy stress in yeast Bexley et al. report that rapid metabolic shifts mediate immediate, protective changes in RNA metabolism following energy depletion. In yeast, protein production is regulated by tuning enzymatic constants to energy charge ratios. This initiates a global shutdown within seconds in response to declining intracellular ATP, independent of the specific cause.

Rapid remodeling of NTP levels enables immediate translational adaptation to energy stress in yeast

Matrin-3 forms spherical and wormlike assemblies that are modulated by RNA binding and ALS/FTD-associated mutations Sprunger et al. have characterized the intrinsically disordered protein Matrin-3, which is implicated in amyotrophic lateral sclerosis (ALS). They find that Matrin-3 forms unusual nanoscale spherical and wormlike assemblies that undergo reversible and concentration-dependent transitions. RNA binding and ALS-associated mutations are key modulators of these assemblies.

Matrin-3 forms spherical and wormlike assemblies that are modulated by RNA binding and ALS/FTD-associated mutations

Biochemical reconstitution of sister chromatid cohesion establishment during DNA replication Genome inheritance during cell divisions relies on replicated sister DNAs being connected by cohesin rings. Minamino et al. reconstitute sister chromatid cohesion establishment during DNA replication using purified budding yeast proteins. The experiments yield molecular insight into more than one way in which sister chromatid cohesion can be built.

Biochemical reconstitution of sister chromatid cohesion establishment during DNA replication

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A Leishmania virulence factor harnesses an allosteric kinase switch to regulate its ubiquitin ligase activity Fokkens et al. identify a eukaryotic module combining kinase and ubiquitin ligase domains. This module is part of a Leishmania virulence factor, TKUL, that requires both enzymatic activities and employs HSP70 adaptors for substrate ubiquitylation. This activity is allosterically controlled by the kinase, enabling suppression of ubiquitylation by kinase inhibitors.

Online Now: A Leishmania virulence factor harnesses an allosteric kinase switch to regulate its ubiquitin ligase activity Online now:

The nuclear pore complex connects energy sensing to transcriptional plasticity in longevity Zhou et al. identify an ancient role of the nucleoporin NUP50 in pro-longevity responses to nutrient stress, independent of its role in nuclear transport. The authors show that nutrient stress activates NUP50 post-translationally, rewiring metabolism and promoting longevity through its intrinsically disordered region, coupling energy sensing to protective transcriptional responses.

Online Now: The nuclear pore complex connects energy sensing to transcriptional plasticity in longevity Online now:

Ubiquitin precursor with C-terminal extension promotes proteostasis and longevity Altin et al. identified CxUb, a C-terminally extended ubiquitin molecule dedicated to overcoming stress and present in all eukaryotic genomes. CxUb marks client proteins for efficient degradation by the proteasome, ensuring cellular quality control. CxUb function is critical specifically in stressed cells, safeguarding healthy ones and contributing to healthy aging.

Online Now: Ubiquitin precursor with C-terminal extension promotes proteostasis and longevity Online now:

Matrin-3 forms spherical and wormlike assemblies that are modulated by RNA binding and ALS/FTD-associated mutations Sprunger et al. have characterized the intrinsically disordered protein Matrin-3, which is implicated in amyotrophic lateral sclerosis (ALS). They find that Matrin-3 forms unusual nanoscale spherical and wormlike assemblies that undergo reversible and concentration-dependent transitions. RNA binding and ALS-associated mutations are key modulators of these assemblies.

Online Now: Matrin-3 forms spherical and wormlike assemblies that are modulated by RNA binding and ALS/FTD-associated mutations Online now:

Rapid remodeling of NTP levels enables immediate translational adaptation to energy stress in yeast Bexley et al. report that rapid metabolic shifts mediate immediate, protective changes in RNA metabolism following energy depletion. In yeast, protein production is regulated by tuning enzymatic constants to energy charge ratios. This initiates a global shutdown within seconds in response to declining intracellular ATP, independent of the specific cause.

Online Now: Rapid remodeling of NTP levels enables immediate translational adaptation to energy stress in yeast Online now:

mtDNA base editing: Mind the gap

Danger zone: The balance between fat-driven health and death Damage to polyunsaturated fats causes ferroptotic cell death. In this issue, Deng et al. show that the incorporation of the fatty acid DHA into membranes is controlled by the protein UBXD8, as a natural mechanism to prevent overloading cells with dangerous fat, preventing ferroptosis.

Danger zone: The balance between fat-driven health and death

Using SPIDRs to map the RNA-protein web In a recent publication in Cell, Wolin et al. describe a massively multiplexed variation of CLIP called SPIDR that allows the simultaneous profiling of targets of arbitrary numbers of RNA-binding proteins. Using SPIDR, they uncover unexpected RNA-protein interactions controlled by the nutrient-regulated mTOR pathway.

Using SPIDRs to map the RNA-protein web

Requirements for establishment and epigenetic stability of mammalian heterochromatin Tatarakis et al. study how H3K9me3 heterochromatin is formed and inherited in mammalian cells. Using a synthetic heterochromatin assembly system and genetic screens, they uncover requirements for initiation and maintenance of silencing, revealing how DNA methylation and chromatin modifiers cooperate to stabilize H3K9me3 heterochromatin.

Requirements for establishment and epigenetic stability of mammalian heterochromatin

The histone chaperone Spt6 controls chromatin structure through its conserved N-terminal domain During transcription, histone chaperones are essential for nucleosome disassembly and reassembly. Warner et al. provide evidence that the Spt6 N-terminal domain is essential for this process. The Spt6 NTD interacts directly with histones and is required for normal chromatin structure. Genetic evidence closely connects Spt6 with the histone chaperone FACT.

The histone chaperone Spt6 controls chromatin structure through its conserved N-terminal domain

RAD23B acquires a copper metalloadaptor function in amphibian-to-reptile evolution to increase metabolism and regulate genomic integrity Xiao et al. identified that RAD23B evolves as metalloadaptor in Amniota to regulate copper homeostasis, thus improving cellular metabolism fitness while protecting cell integrity.

RAD23B acquires a copper metalloadaptor function in amphibian-to-reptile evolution to increase metabolism and regulate genomic integrity