In Saccharomyces cerevisiae, deletion of large ribosomal subunit protein-encoding genes increases the replicative lifespan in a GCN4-dependent manner. However, how GCN4, a key transcriptional activator of amino acid biosynthesis genes, increases lifespan, is unknown. Here we show that GCN4 acts as a repressor of protein synthesis. By analyzing the messenger RNA and protein abundance, ribosome occupancy and protein synthesis rate in various yeast strains, we demonstrate that GCN4 is sufficient to reduce protein synthesis and increase yeast lifespan. Chromatin immunoprecipitation reveals GCN4 binding not only at genes that are activated, but also at genes, some encoding ribosomal proteins, that are repressed upon GCN4 overexpression. The promoters of repressed genes contain RAP1 binding motifs. Our data suggest that GCN4 is a central regulator of protein synthesis under multiple perturbations, including ribosomal protein gene deletions, calorie restriction, and rapamycin treatment, and provide an explanation for its role in longevity and stress response.The transcription factor GCN4 is known to regulate yeast amino acid synthesis. Here, the authors show that GCN4 also acts as a repressor of protein biosynthesis in a range of conditions that enhance yeast lifespan, such as ribosomal protein knockout, calorie restriction or mTOR inhibition.

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Journal Article | Research Support, Non-U.S. Gov't

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Mittal N, Guimaraes JC, Gross T, Schmidt A, Vina-Vilaseca A, Nedialkova DD, Aeschimann F, Leidel SA, Spang A, Zavolan M

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