A viral block on host protein synthesis: As the coronavirus disease 2019 (COVID-19) pandemic continues to cause devastation, scientists race to increase their understanding of the disease-causing severe acute respiratory syndrome coronavirus 2. Once inside host cells, not only does the virus hijack the cells' translational machinery to make viral proteins, but the virulence factor nonstructural protein 1 (Nsp1) also shuts down translation of host messenger RNA. Thoms et al. determined a 2.6-angstrom resolution cryo–electron microscopy structure of a reconstituted complex of Nsp1 bound to the human 40 S ribosomal subunit and showed that Nsp1 blocks the messenger RNA entry tunnel. A structural inventory of native Nsp1-ribosome complexes from human cells confirms this mechanism. Cellular studies show that the translational shutdown almost completely inhibits the innate immune response. The binding pocket on the ribosome may be a target for drugs to treat COVID-19. Science , this issue p. 1249

Coupling translation and mRNA decay: Gene expression requires messenger RNAs (mRNAs)—DNA-derived blueprints of genes—to be translated by protein-producing ribosomes. The levels of mRNAs are tightly regulated, in part by controlling their half-lives. In eukaryotic cells, mRNA half-life is largely linked to translational efficiency, but the mechanism underlying this link has remained elusive. Buschauer et al. used cryo–electron microscopy and RNA sequencing to show how a key regulator of mRNA degradation, the Ccr4-Not complex, monitors the ribosome during mRNA translation. They found that the Not5 subunit directly binds to a ribosomal site exposed specifically during inefficient decoding, thereby triggering mRNA degradation. Analysis of mutants revealed the importance of this sensing mechanism for mRNA homeostasis. Science , this issue p. eaay6912

Cells adjust to nutrient deprivation by reversible translational shutdown. This is accompanied by maintaining inactive ribosomes in a hibernation state, in which they are bound by proteins with inhibitory and protective functions. In eukaryotes, such a function was attributed to suppressor of target of Myb protein 1 (Stm1; SERPINE1 mRNA-binding protein 1 [SERBP1] in mammals), and recently, late-annotated short open reading frame 2 (Lso2; coiled-coil domain containing short open reading frame 124 [CCDC124] in mammals) was found to be involved in translational recovery after starvation from stationary phase. Here, we present cryo-electron microscopy (cryo-EM) structures of translationally inactive yeast and human ribosomes. We found Lso2/CCDC124 accumulating on idle ribosomes in the nonrotated state, in contrast to Stm1/SERBP1-bound ribosomes, which display a rotated state. Lso2/CCDC124 bridges the decoding sites of the small with the GTPase activating center (GAC) of the large subunit. This position allows accommodation of the duplication of multilocus region 34 protein (Dom34)-dependent ribosome recycling system, which splits Lso2-containing, but not Stm1-containing, ribosomes. We propose a model in which Lso2 facilitates rapid translation reactivation by stabilizing the recycling-competent state of inactive ribosomes.

The proper regulation of transcription is essential for maintaining genome integrity and executing other downstream cellular functions^1,2. Here we identify a stable association between the genome-stability regulator sensor of single-stranded DNA (SOSS)³ and the transcription regulator Integrator-PP2A (INTAC)^4–6. Through SSB1-mediated recognition of single-stranded DNA, SOSS–INTAC stimulates promoter-proximal termination of transcription and attenuates R-loops associated with paused RNA polymerase II to prevent R-loop-induced genome instability. SOSS–INTAC-dependent attenuation of R-loops is enhanced by the ability of SSB1 to form liquid-like condensates. Deletion of NABP2 (encoding SSB1) or introduction of cancer-associated mutations into its intrinsically disordered region leads to a pervasive accumulation of R-loops, highlighting a genome surveillance function of SOSS–INTAC that enables timely termination of transcription at promoters to constrain R-loop accumulation and ensure genome stability.