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.

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.

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.

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.

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.

Indeglia et al. describe a new post-translational modification that alters p53 function.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

In this issue of Molecular Cell, Xiang et al. provided insights into the mechanism and structure-guided engineering of DdCBE for mitochondrial DNA base editing. More precise editing was achieved by better defining the editing window.

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.

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.

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.

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.