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New cryo-electron microscopy (cryo-EM) structures of CDP- and CDP-choline-bound choline phosphotransferase 1 (CHPT1) and choline/ethanolamine phosphotransferase 1 (CEPT1), involved in the metabolism of the two main lipids in eukaryotic cell membranes, capture the membrane proteins at resolution <4 Å, sufficient to gain mechanistic insights into these enzymes.
The development of an epigenetics-focused, CRISPR-based high-content functional genomics screening platform provides insight into chromatin regulation and uncovers a potential strategy to treat an aggressive type of leukemia.
New work shows that in mammals, the iDDR motif of telomere factor TRF2 inhibits the MRE11–RAD50–NBS1 (MRN) complex at chromosome ends through a direct iDDR–RAD50 interaction. Unrelated protein motifs in yeasts inhibit MRN functions via an analogous mechanism, suggesting a convergent evolution in eukaryotes to control MRN action at telomeres.
Inactivation of one of the two female X chromosomes involves condensing it into a repressive subnuclear territory, which is depleted of transcriptional components and undergoes late-stage DNA replication. Two new studies unravel how compartmentalization of the inactive mammalian X chromosome affects transcription and DNA replication.
Pioneer transcription factors access gene regulatory sites embedded within chromatin. They drive gene expression programs vital for cell fate decisions and cellular reprogramming, but how they engage nucleosomal sites at the molecular level is unclear. New results show that they engage histones and collaborate to overcome the nucleosome barrier.
NuA4 is a highly conserved histone acetyltransferase complex that functions in transcription and DNA repair. Four groups have recently determined the structure of NuA4 from two different yeasts using cryo-EM, revealing important mechanistic details of its function and allowing a detailed comparison to the related SAGA complex.
Unlike autosomal genes, X-linked genes are expressed from only one copy in both male and female mammals. How cells increase X-linked gene expression to match autosomal levels is unclear. New evidence suggests that lower levels of RNA modifications on X chromosome-derived transcripts critically regulate mRNA stability and help to balance X-to-autosome gene expression levels.
Immunoglobulin M (IgM) is the most ancient antibody class and key mediator of the primary immune response. New structures reveal how it binds to its only class-specific receptor (FcμR) and offer a tantalizing clue to the role of FcμR in the IgM B cell receptor.
A study on a yeast model explores how ssDNA gaps induce cell death and genomic instability, implicating Rad9 and Rad51 in gap repair and protection. Gaps forming secondary structures trigger chromosome fragility, deletions, rearrangements, or cell death pathways, showing how gaps are a vulnerability in cancer cells with opportunity for selective targeting.
Two new structural studies of the GABA transporter subtype GAT1 reveal detailed snapshots of the GABA transport cycle, providing new mechanistic insights and blueprints for rational design of novel leads that target GABAergic systems.
Volume-regulated anion channels (VRACs) are critical for cell volume regulation, neuron–glia interaction, metabolism, and immunity. They are formed as heteromers of LRRC8 proteins with unknown stoichiometry. Two papers now reveal the structures of heteromeric LRRC8A and LRRC8C channels, providing insights into channel assembly and gating.
Gabapentinoids are first-line treatments for chronic pain but are associated with adverse side effects. A cryo-EM structure of gabapentin bound to its interaction site on the calcium channel α2δ subunit now paves the way for the rational design of analgesics with greater selectivity and a reduced potential for adverse effects.
The maturation of transfer RNAs requires the splicing of precursor tRNAs by specific endonucleases. New cryo-electron microscopy studies of the human splicing endonuclease bound to tRNAs shed light on how it cleaves and splices its substrates, explaining the function of eukaryote-specific enzyme subunits and rationalizing disease-associated mutations.
Cilia — or flagella, as they are interchangeably termed — are appendage-like organelles extending from eukaryotic cells. Several recent structural studies on intraflagellar transport (IFT) trains shed light on these fascinating complexes, including their assembly mechanism, stability, cargo recruitment and evolution.
