In this perspective, the authors showcase the importance and need for additional investigation of the ubiquitin-dependent regulation of neurodevelopment. They then propose interdisciplinary approaches that will allow improved spatiotemporal understanding of this relationship in the context of basic neuroscience and disease.

Szalay et al. discuss cross-kingdom similarities and differences in 3D chromatin folding in relation to gene regulation, including in bacteria, archaea, mammals and plants. This comparison reveals certain factors as ancestral sculptors of the genome, but also that evolution tolerates considerable variety in genome organization.

Racetam anticonvulsants, such as levetiracetam, are widely prescribed to treat and prevent seizures. Despite decades of clinical use, their mechanism of action remains unclear. Two studies now reveal the structure of the racetam-binding protein SV2A in complex with anticonvulsant drugs, providing insights into their mechanism of action and the physiology of neurotransmission.

Autoantibodies targeting glutamatergic N-methyl-d-aspartic acid receptors (NMDARs) are found in people with anti-NMDAR encephalitis. Two studies reveal that patient-derived autoantibodies are diverse in their epitope binding and modes of action on the NMDAR, providing insights into the mechanisms behind autoantibody-induced NMDAR hypofunction.

Using cryo-electron microscopy and biochemical analysis, the authors reveal the mechanism of transcriptional inhibition by the noncoding RNA Alu and provide insights into relief of inhibition by the general transcription factor TFIIF.

Combining structural, biochemical, cellular and in vivo assays, the authors uncover the mechanism for capture and multisite phosphorylation of lethal (2) giant larvae by the atypical protein kinase C and partitioning-defective protein 6, revealing the basis for their mutual antagonism underpinning cell polarity.

In this study, the authors show that DNA-damage-mediated transcriptional stress induces NF-κB through IRAK1, allowing damaged cells with impaired transcription to initiate an inflammatory response without relying on their gene expression.

The study highlights the importance of water-mediated interactions in recognition of dinucleotides by transcription factors. Water’s influence on enthalpy and entropy modulates binding affinity and temperature sensitivity of TF binding.

Bhatta et al. use biochemistry and cryogenic electron microscopy to elucidate the mechanism of human tRNA 3′ processing. Their results show how mitochondria-specific subunits of RNase Z compensate for the structural degeneracy of organellar tRNAs.

Here the authors show that codependence of dynein and kinesin KIF1C occurs through binding of the FTS–HOOK3–FHIP1B cargo adapter. Binding of KIF1C releases the HOOK3 autoinhibited folded conformation allowing dynein to bind the adapter. In this cocomplex, KIF1C further acts as a processivity factor for dynein.

As 2024 closes, we take this opportunity to reflect on the highlights of our 30th anniversary year and consider what the future holds for the field.