The Gcn4 transcription factor reduces protein synthesis capacity and extends yeast lifespan
Nitish Mittal,Joao C. Guimaraes,Thomas Gross,Alexander Schmidt,Arnau Vina-Vilaseca,Danny D. Nedialkova,Florian Aeschimann,Sebastian A. Leidel,Sebastian A. Leidel,Anne Spang,Mihaela Zavolan +10 more
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TLDR
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.Abstract:
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.read more
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Protein synthesis rates and ribosome occupancies reveal determinants of translation elongation rates.
Andrea Riba,Noemi Di Nanni,Noemi Di Nanni,Nitish Mittal,Erik Arhné,Alexander Schmidt,Mihaela Zavolan +6 more
TL;DR: It is found that the amino acid composition of synthesized proteins is as important a determinant of translation elongation rate as parameters related to codon and transfer RNA (tRNA) adaptation.
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Gene regulatory network reconstruction using single-cell RNA sequencing of barcoded genotypes in diverse environments.
TL;DR: A framework for learning gene regulatory networks from scRNAseq data that incorporates multitask learning is benchmarked and a global gene regulatory network comprising 12,228 interactions is constructed.
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A Conserved Mito-Cytosolic Translational Balance Links Two Longevity Pathways
Marte Molenaars,Georges E. Janssens,Evan G. Williams,Aldo Jongejan,Jiayi Lan,Sylvie Rabot,Fatima Joly,Perry D. Moerland,Bauke V. Schomakers,Marco Lezzerini,Yasmine J. Liu,Mark A. McCormick,Brian K. Kennedy,Brian K. Kennedy,Michel van Weeghel,Antoine H. C. van Kampen,Ruedi Aebersold,Ruedi Aebersold,Alyson W. MacInnes,Riekelt H. Houtkooper +19 more
TL;DR: It is demonstrated that inhibiting mitochondrial translation initiates an atf-5/ATF4-dependent cascade leading to coordinated repression of cytosolic translation, which could be targeted to promote longevity.
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Ssd1 and Gcn2 suppress global translation efficiency in replicatively aged yeast while their activation extends lifespan.
Zheng Hu,Bo Xia,Spike D. L. Postnikoff,Zih Jie Shen,Alin Tomoiaga,Alin Tomoiaga,Alin Tomoiaga,Troy A. A. Harkness,Ja Hwan Seol,Wei Li,Kaifu Chen,Kaifu Chen,Jessica K. Tyler +12 more
TL;DR: TRNA overexpression sufficed to extend lifespan in an autophagy-dependent manner in the absence of changes in global translation, indicating that Gcn4-mediatedAutophagy induction is the ultimate downstream target of activated Gcn2, to extended lifespan.
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A new experimental platform facilitates assessment of the transcriptional and chromatin landscapes of aging yeast.
David G. Hendrickson,Ilya Soifer,Bernd Wranik,Griffin Kim,Michael Robles,Patrick A. Gibney,R. Scott McIsaac +6 more
TL;DR: Combining MAD with an improved ATAC-seq method, it is found that increasing proteasome activity reduces rDNA instability usually observed in aging cells and, contrary to published findings, provide evidence that global nucleosome occupancy does not change significantly with age.
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