Browse Articles

Here, the authors describe 3D hubs as regulatory subunits of gene expression in the three essential lineages of embryogenesis. They develop a computational model that can predict novel enhancers and they validate such enhancers in the context of specific lineages.

Transcription factors are rich in intrinsic disorder and therefore hard to drug. The authors improve an experimental drug for castration-resistant prostate cancer by learning how the activation domain of the androgen receptor activates transcription.

In this Review, the authors discuss the various ways that alternative splicing sculpts the landscape of protein interactions with their partners, essentially all types of biomolecules, and the implications of alternative interactions at the molecular, cellular and disease level.

We describe how transcription start site (TSS) choice of thousands of genes results in transcript isoforms with potential for distinct post-transcriptional regulation affecting translation and cell behavior. We show that dynamic switching between initiation sites defines cancer proliferation, differentiation and treatment response, indicating start site determination as a potential diagnostic tool.

DNA polymerase θ (POLQ) repairs mitotic DNA breaks; this requires RHINO and PLK1, averts genomic instability and may underlie effects of POLQ inhibitors in HDR-deficient cancer cells. We discuss recent work on mitotic DNA break processing and repair, the need for multiple DSB repair pathways and implications of therapeutic POLQ targeting in cancer.

Here, using CAGE-seq, the authors show that transcription start site choice in thousands of genes may endow transcripts with distinct post-transcriptional fates, with dynamic switching defining cancer cell proliferation, differentiation and treatment response.

An Ago2^HA/HA mouse model combined with super-resolution microscopy, molecular and biochemical assays allowed us to stringently characterize AGO2 regulation in vivo. We found that in quiescent splenocytes, AGO2 localizes almost exclusively to the nucleus, where it binds to the RNA of young mobile transposons and represses their expression through its catalytic domain.

Here the authors show that, in the absence of Pi3K–AKT–mTOR signaling, AGO2 accumulates in the nucleus of quiescent cells, where it binds to young retrotransposons and represses their expression.

The human ATPase p97 (also known as VCP) unfolds protein substrates by translocating them through its central channel. This process is highly regulated by numerous adapter proteins. Structures of p97 in complex with the unusual adapter UBXD1 reveal how this protein coordinates p97 hexamer remodeling and ring opening by expansive interactions across multiple p97 protomers.

Ferroptosis suppressor protein 1 (FSP1, or AIFM2), an NADPH quinone reductase noted to protect cancer cells from ferroptosis, acts in FAD/NADPH binding and proton transfer. Recent papers assess its evolutionarily conserved sites via mutagenesis and define its inhibition as an off-target mediator of brequinar-mediated ferroptosis sensitization.

OAT1 has a fundamental role in the kidney by facilitating the urinary excretion of various drugs and endogenous metabolites. Two studies now present high-resolution structures of OAT1 using cryo-EM, elucidating its intricate polyspecific transport capabilities and paving the way for structure-based drug research and development.

Mao et al. reported ribosomal frameshifting events shortly after start codon selection, which is influenced by the sequence context and controlled by initiation factor eIF5B. This translational ‘noise’ is increased in response to nutrient starvation.

Extensive mutational analyses of ferroptosis suppressor protein-1 (FSP1) reveal its molecular mechanism in ferroptosis prevention and uncover the mechanism of action of the FSP1 inhibitor iFSP1 and a new species-independent FSP1 inhibitor, viFSP1.

Many multipass membrane proteins are not fully inserted into the membrane when translation ends. Wu et al. now show that a membrane insertase called EMC can facilitate maturation of these proteins by post-translationally completing their insertion.

Cryogenic electron microscopy structures reveal how the immunophilin co-chaperones, FKBP51 and FKBP52, each engage Hsp90–client complexes to directly stabilize a folded, ligand-bound client, the glucocorticoid receptor, and promote the next stage of client maturation.

Braxton et al. report structures of human p97/VCP bound to the UBXD1 adaptor involved in autophagy. The structures reveal how UBXD1 utilizes multiple interaction domains to remodel and open the hexamer ring, revealing its role in p97 regulation.

The authors reveal the architecture and functional annotation of large immunophilin-containing Hsp90–apo-GR complexes by systematic incorporation of photocrosslinker inside human cells and show that FKBP51 and FKBP52 differentially interact with the apo-GR.

Using cryo-EM, here the authors structurally delineate the Elongin–RNA polymerase II holocomplex. They show that Elongin allosterically regulates the transcribing RNA polymerase II via a latch that affects its conformational mobility.