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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

Methionine adenosyltransferase (MAT) catalyzes the synthesis of S-adenosylmethionine (SAM). As the sole methyl-donor for methylation of DNA, RNA, and proteins, SAM levels affect gene expression by changing methylation patterns. Expression of MAT2A, the catalytic subunit of isozyme MAT2, is positively correlated with proliferation of cancer cells; however, how MAT2A promotes cell proliferation is largely unknown. Given that the protein synthesis is induced in proliferating cells and that RNA and protein components of translation machinery are methylated, we tested here whether MAT2 and SAM are coupled with protein synthesis. By measuring ongoing protein translation via puromycin labeling, we revealed that MAT2A depletion or chemical inhibition reduced protein synthesis in HeLa and Hepa1 cells. Furthermore, overexpression of MAT2A enhanced protein synthesis, indicating that SAM is limiting under normal culture conditions. In addition, MAT2 inhibition did not accompany reduction in mechanistic target of rapamycin complex 1 activity but nevertheless reduced polysome formation. Polysome-bound RNA sequencing revealed that MAT2 inhibition decreased translation efficiency of some fraction of mRNAs. MAT2A was also found to interact with the proteins involved in rRNA processing and ribosome biogenesis; depletion or inhibition of MAT2 reduced 18S rRNA processing. Finally, quantitative mass spectrometry revealed that some translation factors were dynamically methylated in response to the activity of MAT2A. These observations suggest that cells possess an mTOR-independent regulatory mechanism that tunes translation in response to the levels of SAM. Such a system may acclimate cells for survival when SAM synthesis is reduced, whereas it may support proliferation when SAM is sufficient.