In this issue of Molecular Cell, Bobadilla Ugarte et al.1 show that ACE1, a Cas4-family nuclease, partners with prokaryotic Argonautes to generate guide DNAs, revealing a dedicated siDNA biogenesis pathway in cyanobacterial immune systems.

In this issue of Molecular Cell, Lu et al.1 report conserved global translation suppression by Prkra, also known as PACT in humans, in response to double-stranded RNA stimulation. Prkra directly binds to RNA and sequesters eIF2 complexes in a PKR-independent manner.

Ribosome biogenesis is a complex and error-prone process, necessitating quality control mechanisms to degrade defective pre-ribosomal intermediates. In this issue of Molecular Cell, Akers et al.1 report the identification of a previously uncharacterized quality control pathway named ribosome assembly surveillance pathway (RASP), which functions to eliminate aberrant "dead-end" pre-60S assembly intermediates

The function of the proteasome besides degrading protein remains enigmatic. Goldberg et al. demonstrate that proteasomes can process proteins into antimicrobial peptides (AMPs) to ward off bacterial infection,1 revealing a new function of proteasomes in innate immunity.

Uracil incorporation into DNA, as a result of nucleotide pool imbalances or cytosine deamination (e.g., through APOBEC3A/3B), can result in replication stress and is the most common source of mutations in cancer and aging. Despite the critical role of uracil in genome instability, cancer development, and cancer therapy, only now is there emerging data on its impact on fundamental processes such as

The regulation of RNA polymerase II (RNAPII) activity requires orchestrated responses among genomic regulatory sequences and an expansive set of proteins and protein complexes. Despite intense study over five decades, mechanistic insights continue to emerge. Within the past 10 years, live-cell imaging and single-cell transcriptomics experiments have yielded new information about enhancer-promoter communication

We talk to authors Sukrit Silas and Héloïse Carion about their paper “Activation of bacterial programmed cell death by phage inhibitors of host immunity” (in this issue of Molecular Cell) and the mutagenesis screen that it arose from.

In this issue of Molecular Cell, He et al.1 and Yang et al.2 unexpectedly find that inhibitors of pre-mRNA splicing induce cell death via formation of RNA-RNA/DNA-RNA hybrids in Z conformation. These Z-nucleic acids are recognized by the protein ZBP1, which activates innate immune signaling.

Small noncoding RNAs typically regulate the translation initiation of target mRNAs and thereby protein production. In this issue of Molecular Cell, Thongdee et al. discovered a novel regulatory mechanism where a bacterial small RNA modulates translation elongation and co-translational folding to alter protein activity without affecting protein abundance.

A recent study1 unveils tandem interspaced guide RNAs (TIGRs) that simultaneously engage both strands of target DNA and direct Tas protein activity. It offers insights into the evolution of RNA-guided proteins and introduces a promising tool for genome editing.

In this issue of Molecular Cell, Schärfen et al.1 describe an advanced RNA structure-probing technology called CoSTseq that enables transcriptome-wide detection of nascent RNA base pairing during transcription in living yeast cells.

In this issue, Guo et al.1 and Chen et al.2 resolved the cryo-EM structures of G protein-coupled receptor (GPR) 4 and GPR68, unveiling that histidine protonation initiates conformational rearrangements and dictates G protein coupling bias, illuminating pH-sensing mechanisms.

In a recent issue of Molecular Cell, Genoyer et al.1 show that during West Nile virus infection, escaped, cytoplasmic, anti-genomic negative-sense viral RNA triggers an antiviral response via RIG-I activation. Flaviviruses typically hide −vRNA in replication compartments to avoid detection, but some −vRNA leaks, possibly aided by viral capsid proteins.

Recent elegant studies in Nature1,2 uncovered an unprecedented molecular glue-like mechanism of action for the preclinical drug UM171. This small molecule showed striking functional and structural similarities to brain cancer mutations that prompt neomorphic protein interactions. This phenomenon of chemical-genetic convergence could be reverse-engineered to aid the rational design of induced proximity

Mitochondria serve as central hubs in cellular metabolism by sensing, integrating, and responding to metabolic demands. This integrative function is achieved through inter-organellar communication, involving the exchange of metabolites, lipids, and signaling molecules. The functional diversity of metabolite exchange and pathway interactions is enabled by compartmentalization within organelle membranes

In this issue, Huang et al.1 report the acetylation of METTL3 as a negative regulator of m6A deposition of chromatin-associated regulatory RNAs from enhancers and promoters. This acetylation is mediated by p300 and positively regulated by PAK2.

In this issue of Molecular Cell, Tang et al.1 demonstrate that the ketone body β-hydroxybutyrate (BHB) promotes the biogenesis of mitochondrial-derived vesicles (MDVs) via lysine β-hydroxybutyrylation (Kbhb) on SNX9, revealing a way to fine-tune the mitochondrial quality control pathway with metabolites.

In this issue of Molecular Cell, Kiss et al.1 introduce UbiREAD, a technology that deciphers ubiquitin chain-mediated degradation in living cells, revealing a hierarchy where K48 chains of at least three ubiquitins drive rapid proteasomal degradation and branched K48/K63 chains follow substrate-anchored rules.

Cancer cells subvert the immune system by reprogramming their metabolism. In a recent study in Nature, Ikeda et al.1 show how cancer cells can directly transfer mitophagy-resistant mitochondria to tumor-infiltrating lymphocytes, promoting their homoplasmic replacement and undermining cancer immunity.

Enzyme design has struggled to emulate the complexity and catalytic proficiency of natural enzymes. Lauko et al.1 show that with the help of deep learning, the design of serine hydrolases that rival nature’s ingenuity is possible.