Browse Articles

To ensure accurate gene expression, transcription-coupled repair (TCR) clears DNA transcription blocks, yet genotoxic insults also damage RNA. A study shows that Integrator subunit INTS12 is a key mediator linking ribosome-mediated damage signaling to TCR, with stress-induced phosphorylation promoting clearance of stalled RNA polymerase II.

Burr and Auckland et. al develop MitoPerturb-Seq, which combines single-cell screening with multiomics to link nuclear genes to mitochondrial DNA (mtDNA) dynamics. They unveil core regulators of mtDNA copy number and characterize cell-cycle delays and transcriptional stress in response to mtDNA depletion.

Dutta et al. demonstrate that the tumor suppressor complex BRCA1–BARD1 physically interacts with the RNA–DNA helicase Senataxin (SETX) and upregulates the activity of SETX to resolve harmful R-loops crucial for the avoidance of transcription–replication conflicts.

Liu et al. show that the C9orf72 GGGGCC-repeat RNA drives liquid-to-solid phase transition of poly(GR) in ALS/FTD through forming G-quadruplex and hairpin scaffolds, whereas targeting the RNA structures with small molecules reduces poly(GR) aggregation and cellular dysfunction.

Wang, Guo, Zhang and colleagues obtain four cryo-electron microscopy snapshots that show how IscB is kept off by two RNA lids, with a car-pedal-like guide shift activating cleavage after ~11-nt pairing. They also engineer hinge regions that boost flexibility and improve genome editing in cells.

High-fidelity CRISPR–Cas9 enzymes have fewer off-targets but often suffer from low editing efficiency. Here, we show that a simple extension of the guide RNA improves the activity of SuperFi-Cas9 while preserving its accuracy. This extension enhances SuperFi-Cas9’s genome editing performance by strengthening the interactions in the protospacer adjacent motif (PAM)-distal region.

In this issue of Nature Structural & Molecular Biology, we focus on all things protein homeostasis, highlighting a variety of processes, from protein quality control in translation to autophagy.

Zheng et al. show that extending the guide RNA restores the reduced activity of a high-fidelity CRISPR–Cas9 enzyme while preserving accuracy, revealing how strengthened PAM-distal interactions can improve genome-editing performance.

Here the author highlights and summarizes the latest advances in ribosome-associated quality control and related mechanisms.

The oxidoreductase FSP1 recycles radical-trapping antioxidants that suppress oxidative lipid damage and ferroptosis. A series of genetic screens reveal a key role for the vitamin B2 metabolite flavin adenine dinucleotide in stabilizing FSP1, preventing its proteasomal degradation and promoting ferroptosis suppression.

Protein homeostasis is essential for cell health and function, with the proteostasis network safeguarding protein production, folding and degradation. Disruption of any of the multiple pathways involved is a hallmark of aging and many pathologies. We asked experts studying proteostasis to share with us which unresolved questions they are most interested in addressing and how they envision the field in the future.

Here, Deol et al. use genetic screens in gene-edited reporter cell lines to identify regulators of ferroptosis suppressor protein 1 (FSP1) expression and stability. They show that vitamin B2 metabolism stabilizes FSP1 through flavin adenine dinucleotide binding, preventing its degradation and ferroptosis sensitization.

Peptidyl arginine deaminase 6 (PADI6) is an essential maternal protein in oocytes, and PADI6 variants have been previously linked to female infertility. Here, we report that PADI6 sequesters the E2 ubiquitin-conjugating enzyme UBE2D with assistance from the E3 ubiquitin ligase UHRF1, thereby inhibiting protein ubiquitination in oocytes. Our identified maternal PADI6–UHRF1–UBE2D complex (which we termed the MPU complex) provides a mechanistic explanation for why certain PADI6 variants have been associated with female infertility.

The partnership between a leading European research institute, the European Molecular Biology Laboratory (EMBL), and a pharmaceutical company, GSK, has set an example of how to build a successful academia–industry relationship. Here, we reflect on the key success factors that shaped this partnership.

METALoci, a computational framework to study the 3D genome, reveals a prominent rewiring of regulatory interactions during sex determination. This geostatistics-inspired method also uncovered a previously unknown non-coding regulatory region at the Fgf9 locus and identifies Meis genes as crucial regulators of sex differentiation.

Many protein–protein interactions are mediated by compact amino acid stretches known as short linear motifs (SLiMs) that lack a stable tertiary structure. A study now uses high-throughput precision genome editing to decode the function of over 7,000 SLiMs across the human proteome, providing insights into their roles in cellular homeostasis.

Ambjørn and Meeusen et al. functionally characterize all reported and a comprehensive set of predicted short linear motifs (SLiMs) using base-editing screens, identifying 450 reported and 264 predicted SLiMs required for normal cell proliferation.

In this review, the authors discuss and contextualize the cellular responses launched after mitochondrial stress and note the importance of the emerging understanding in applying this new knowledge in relevant diseases.

Here, Li, Lu, Xia and colleagues identify the maternal complex MPU (PADI6–UHRF1–UBE2D), determine its cryo-electron microscopy structure and show that PADI6 maintains oocyte proteostasis by sequestering UBE2D with the assistance of UHRF1, thereby inhibiting protein ubiquitination. The study, thus, provides a molecular mechanism underlying PADI6-associated female infertility.