The Gcn4 Transcription Factor Reduces Protein Synthesis Capacity and Extends Yeast Lifespan [RNA-Seq]

In Saccharomyces cerevisiae, deletion of genes encoding proteins of the large ribosomal subunit (RPLs) 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 mRNA and protein abundance, the ribosome occupancy and protein synthesis rate in various yeast strains, we demonstrate that Gcn4 is sufficient to reduce protein synthesis and to increase yeast lifespan. Chromatin immunoprecipitation reveals Gcn4 binding not only at genes that are activated, but also at genes 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 (RP) gene deletions, calorie restriction, rapamycin treatment - and provide an explanation for its role in longevity and stress response. Overall design: Examination of transcriptome and ribosome occupancy in five different RPKO strains and wild type. Examination of transcriptome in two GCN4-overexpressing strains, one GCN4-mutant strain and respective wild type.

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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