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Identifying a non-enzymatic method of replicating RNA for multiple cycles has been problematic because rapid strand reannealing outcompetes slow non-enzymatic template copying. Now, oligoarginine peptides have been shown to inhibit reannealing while still allowing short primers and activated monomers to bind to the template strand, facilitating the next round of template copying.

Structural, genetic, functional and biochemical analyses of the complex flagellar motor of Campylobacter jejuni reveal structural adaptations with an ancient origin also found more widely across bacterial species, including elements exapted from the type IV pilus machinery.

An RNA aptamer and a ribozyme are both observed to retain a surprising degree of activity despite backbone heterogeneity caused by the presence of non-natural 2′–5′ phosphodiester linkages. These results suggest that absolute regioselectivity of non-enzymatic replication may not have been required for the emergence of RNA as the first biopolymer.

The authors find that TDP-43 loss of function—the pathology defining the neurodegenerative conditions ALS and FTD—induces novel mRNA polyadenylation events, which have different effects, including an increase in RNA stability, leading to higher protein levels.

Smargon et al. show that small nuclear RNAs can improve the cellular safety and efficacy of endogenous protein-mediated RNA base editing, enhancing nuclear RNA editing and the rescue of premature termination codon disease.

Polygenic risk scores can help identify individuals at higher risk of type 2 diabetes. Here, the authors characterise a multi-ancestry score across nearly 900,000 people, showing that its predictive value depends on demographic and clinical context and extends to related traits and complications.

Type I-C Cascade (the CRISPR-associated complex for antiviral defense) is a minimal system, comprising only three unique Cas proteins. Cryo-EM structure of the Desulfovibrio vulgaris type I-C Cascade reveals the molecular mechanisms that underlie RNA-directed complex assembly.

Long-range intragenomic RNA–RNA interactions in the genomes of positive-strand RNA viruses involve direct nucleotide base pairing and can span distances of thousands of nucleotides. In this Review, Nicholson and White discuss recent insights into the structure and function of these genomic features and highlight their diverse roles in the gene expression and genome replication of positive-strand RNA viruses.

I-D CRISPR-Cascade can target both single-stranded and double-stranded nucleic acids. Here, Schwartz et. al determine these structures and reveal large-scale rearrangements that allow for target discrimination and destruction.

Using cryo-electron microscopy, insights into the structural and mechanistic function of the DdmDE system that is responsible for plasmid elimination in Vibrio cholerae seventh pandemic strains are explored.

Ocampo et al. present several structures and the biochemical characterization of a compact Cas9 nuclease, shedding light on how these enzymes function and evolve.

Cryo-electron microscopy structures of Cas9 during mismatch cleavage provide insight into the mechanisms that control off-target effects of Cas9, which will aid in the future design of high-fidelity Cas9 variants with reduced off-target cleavage.

Several existing algorithms predict the methylation of DNA using Nanopore sequencing signals, but it is unclear how they compare in performance. Here, the authors benchmark the performance of several such tools, and propose METEORE, a consensus tool that improves prediction accuracy.

A six-letter sequencing workflow can simultaneously detect genetic and epigenetic bases.

In this study, the authors develop a flavivirus vaccine strategy by introducing mutations into envelope glycoproteins resulting in structural changes that conceal the ADE-prone fusion loop epitope. They show that the Zika virus-specific construct protects mice against viral challenge and prevents ADE by Dengue virus.

Membrane proteins often form clusters that shape membrane function. Here, authors determine the cryo-EM structure of human Stomatin in its native membrane, revealing how it assembles into a ring-like complex that organizes a distinct membrane microdomain.

CRISPR-Cas9 is a powerful tool, but the strict requirement for an “NGG” protospacer-adjacent motif (PAM) sequence limits the number of editable genes. Here the authors combine enzyme kinetics, cryo-EM, and single-molecule imaging to determine how SpRY interrogates DNA and recognises target sites for cleavage.

Structural analysis of Cas12a2, a CRISPR-associated nuclease that nonspecifically cleaves ssRNA, ssDNA and dsDNA, reveals a complete activation pathway involved in the abortive infection system protecting cells against invasion.

A newly developed monoclonal antibody, MARV16, broadly neutralizes all Marburg virus isolates and provides effective protection in guinea pigs with Marburg virus disease.

Light-Seq uses light-directed DNA barcoding in fixed cells and tissues for multiplexed spatial indexing and subsequent next generation sequencing. This approach blends spatial and omics information to enable analysis of rare cell types in complex tissues.

The development of cells requires a mechanism to support homeostasis—the maintenance of constant internal conditions—as cellular growth results in internal dilution. Now, a simple physical process is described in which short oligonucleotide inhibitors enable dilution-driven activation of encapsulated ribozymes via membrane growth, suggesting homeostatic mechanisms could have existed in the earliest cells.

A novel variant annotation metric that quantifies the level of expression of genetic variants across tissues is validated in the Genome Aggregation Database (gnomAD) and is shown to improve rare variant interpretation.

Amino acid changes in the envelope and non-structural 2A protein attenuate the virulent yellow fever virus (YFV) and enhance host antiviral responses upon infection in vivo. These traits explain the potency of the YFV vaccine.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

CRISPR systems entered clinic for therapeutic genome editing, but safety concerns remain. Here, Degtev, Bravo et al. engineer the PsCas9 enzyme, achieving high editing efficacy and maintaining high-fidelity properties, introducing it as a promising tool for safe in vivo genome editing applications.

A previously unsampled deep lineage in central Argentina was discovered that had distinctive genetic drift by 8,500 bp and persisted as the main Native American ancestry component in the region up to the present day.

POLRMT is key for transcription of the mitochondrial genome, yet has not been implicated in mitochondrial disease to date. Here, the authors identify mutations in POLRMT in individuals with mitochondrial disease-related phenotypes and characterise underlying defects in mitochondrial transcription.

Structural analysis of the uridyl transferases TUT4 and TUT7 reveals the use of two functional modules in the switch from monouridylation of pre-let-7, which promotes let-7 expression, to oligouridylation of pre-let-7, which marks it for degradation.

RNA polymerase II has an unexpected function in the nucleolus, helping to drive the expression of ribosomal RNA and to protect nucleolar structure through a mechanism involving triplex R-loop structures.

A few bacterial Cas9 nucleases have been repurposed as genome editing tools. Here, the authors use bioinformatic and biochemical analyses to characterize 79 Cas9 proteins, revealing substantial functional diversity and thus expanding the available toolbox of RNA-programmable CRISPR-associated nucleases.