Reviews & Analysis

Here, the authors describe the composition, architecture, functions and mechanisms of the SMC (structural maintenance of chromosomes) complex Smc5/6 in chromosomal replication and repair, as well as its involvement in disease.

Cryo-electron microscopy (EM) structures and molecular dynamics simulations of organic cation transporters (OCTs) in ligand-free and drug-bound states provide insights into drug recognition by OCTs. As OCTs are largely responsible for the hepatic uptake and renal clearance of hundreds of drugs, these results will help to inform future drug design and development efforts.

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.

The correction of errors during mitochondrial DNA replication by the proofreading function of DNA polymerase-γ is crucial for maintaining the integrity of the mitochondrial genome and the production of cellular energy. Using cryo-electron microscopy, several steps of the DNA polymerase-γ proofreading pathway have been revealed at near-atomic resolution.

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.

The enzymatic activity of PARP1—which adds chains of (poly-ADP)-ribose (PAR) to proteins—initiates DNA repair by leading to more-accessible chromatin and recruitment of PAR-dependent DNA-repair proteins. New work shows that these PARP1-catalysed functions are redirected by the auxiliary factor HPF1 in cells.

Single-molecule live-cell imaging of the transcription dynamics in budding yeast cells revealed that the remodeling of different nucleosomes in the promoter of a gene regulates various kinetic steps of transcription. The measurements also showed that the TATA-binding protein competes with promoter-associated nucleosomes around the TATA element to activate transcription.

We determined the structure of the Polα–primase complex trapped in a DNA elongation state. Cryo-electron microscopy showed that primase has a role in facilitating the timely termination of primer DNA elongation by Polα by hanging on the primer–template complex.

White adipose tissue secretes the small polypeptide hormone leptin, which controls food intake and satiety. Unlike other metabolic hormones such as insulin and glucagon, leptin does not act on the major metabolic organs liver, muscle, and white adipose tissue, but instead exerts its primary function on the central nervous system.

A cardinal rule of DNA replication is to prevent any possibility of pre-replication complexes re-loading during S phase, risking genotoxic over-replication. But can this rule be broken in emergency situations to preserve genome integrity?

Endogenous retroviruses (ERVs), a type of transposable element (TE), have been incorporated throughout evolution into the human genome. We show that many ERVs regulate placental gene expression, which may have helped fuel the rapid evolution of the placenta and could have implications for pregnancy complications.

The cryo-EM structure of a natural AlkB–AlkG fusion from Fontimonas thermophila reveals the mechanistic basis for its selectivity towards, and functionalization of, alkane terminal C–H groups. AlkB contains an alkane entry tunnel and a diiron active site, and AlkG docks through electrostatic interactions and transfers electrons to the diiron center for catalysis.

The RNA methyltransferase (MTase) METTL1 catalyzes N⁷-methylguanosine (m⁷G) modification at position 46 in human transfer RNAs (tRNAs). Its dysregulation drives tumorigenesis in many cancer types. Two papers now reveal the structural basis of this tRNA maturation event.