Reviews & Analysis

mTORC1 promotes cell growth by sensing nutrients and driving anabolic processes. When nutrients are scarce, GATOR1 turns off growth signals. Our study describes how KICSTOR links GATOR1 to lysosomes to enable its function, a finding that may help us to understand certain neurological disorders.

Cell death contributes to tissue homeostasis and plays critical roles in inflammation and host defense. Our increasing understanding of the physiological importance of cell death underlines the need to more fully elucidate its underlying mechanisms in health and disease. Molecular and structural insight into the cell death apparatus could provide strategies to target the loss of cells in pathophysiological contexts. We asked experts studying a range of cell death types to share with us what they are most excited to tackle and what the field needs for progress.

Transfer RNAs (tRNAs) are best known for their role in decoding messenger RNA codons and translating them into amino acids. A comprehensive biochemical and structural investigation of the poxviral transcription apparatus uncovers a thus far unknown role of specific host tRNAs as assembly chaperones for a multisubunit RNA polymerase complex.

We developed an efficient transposon-based approach to create a panel of large genomic rearrangements between lamina associated domains (LADs) and inter-LAD sequences. This work demonstrates that LAD–nuclear lamina interactions involve multiple contacts of varying strength. Moreover, changes in nuclear lamina association are often accompanied by transcriptional repression and heterochromatin histone mark deposition.

To start, or not to start, that is the recurring question faced by eukaryotic ribosomes as they scan mRNA for translation start sites. A study now shows that two opposing initiation factors, which bind the ribosome in a mutually exclusive manner, assist in this decision-making process.

Protein sequence signatures suggest that eons ago, a bacterial glutamate transporter lost its sodium coupling to make way for a shift to proton coupling. A study now maps this ancient transition in biochemical and structural detail to better understand how secondary transporters control their energetics.

Break-induced replication (BIR) is a crucial DNA double-strand break-repair pathway, but it also introduces mutations linked to cancer and genetic disorders. This Review discusses BIR regulation in mammalian cells, its roles in human disease and its potential uses in genome engineering.

The transcription factor GAGA factor (GAF) recruits chromatin remodelers to establish and maintain open chromatin for transcription in Drosophila melanogaster. In searching for DNA targets, GAF undergoes one-dimensional (1D) diffusion on linear DNA; however, 1D diffusion is constrained when DNA is wrapped around histones, necessitating 3D diffusion to locate cognate GAGAG sequences embedded within nucleosomes.

A study reveals how the TRAPPIII complex and Atg2 establish membrane contact sites between the growing autophagosomal membrane and the endoplasmic reticulum, coordinating Rab GTPase signaling and lipid transfer to drive autophagosome formation.

A recent high-resolution structure of USP30 bound to a selective inhibitor identifies a cryptic binding pocket formed through a conformational switch in the catalytic domain of the enzyme. This mechanistic insight opens a door to structure-guided design of mitophagy-enhancing compounds.

By leveraging long-read sequencing, single-cell input scNanoHi-C2 systematically delineates chromatin structural reprogramming in embryonic-stage germ cells (EGCs), highlighting the functional importance of three-dimensional (3D) genome structure in mammalian EGC development. This method provides a powerful tool for probing chromatin architecture in individual cells, particularly in rare or precious biological samples.

Sudden loss of lysosomal acidity triggers a rapid response. Two studies now identify the metazoan RAVE (mRAVE) complex as essential for V-ATPase reassembly and activation under such conditions; map interactions between mRAVE and V-ATPase; and identify a link to CASM, a non-canonical autophagy pathway.

Efficient mitophagy is essential for neuronal health. A study now shows that loss of VPS13D in neurons impairs mitochondrial clearance, gasdermin E activation, mitochondrial DNA release and microglial STING signaling. This neuroimmune mechanism promotes microglial responses that lead to neuronal dysfunction and loss.

How metabolic fitness in cancer clones is established and selected during dissemination and colonization remains enigmatic. A study in Nature now shows that disseminated pancreatic cancer cells bifurcate to seed the lung or liver on the basis of PCSK9 levels and the availability of microenvironmental cholesterol.

Maturation of snRNAs, key parts of the spliceosome, involves nuclear export of newly synthesized snRNAs to the cytoplasm. PHAX is known to mediate snRNA export in a phosphorylation-dependent manner, but the underlying mechanism remains elusive. A cryo-EM structure of a PHAX-containing snRNA export complex now provides insights into the pathway.

Here, the authors comprehensively discuss the different mechanisms for origin licensing in yeast and human cells. Importantly, they present intuitive videos illustrating such mechanisms with unprecedented detail.

Radial spokes link the doublet microtubules at the periphery of the cilium to the central pair complex at its core. The detailed morphology and function of the radial spoke 3 (RS3) complex was unknown, but a new study reports its structure and reveals its role in metabolism.

We created an assay to simultaneously measure the effects of variants in secreted proteins at scale. We used the assay to map the effects of all possible missense variants on factor IX secretion and γ-carboxylation. The resulting data reclassified more than 60% of variants of uncertain significance in hemophilia B.

Constitutive heterochromatin can promote piRNA transcription, a crucial step in genome defense. Two studies now show that piRNA transcription in Drosophila is regulated by the dual histone marks H3K27me3 and H3K9me3, and piRNA transcription in Caenorhabditis elegans is enhanced by H3K27me3, gene clustering and phase separation.