The GATA Transcription Factor Gaf1 Represses tRNAs, Inhibits Growth, and Extends Chronological Lifespan Downstream of Fission Yeast TORC1

María Rodríguez-López,Suam Gonzalez,Olivia Hillson,Edward Tunnacliffe,Sandra Codlin,Victor A Tallada,Jürg Bähler,Charalampos Rallis

doi:10.1016/j.celrep.2020.02.058

María Rodríguez-López, Suam Gonzalez + Show 6 more

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https://doi.org/10.1016/j.celrep.2020.02.058

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Abstract

SummaryTarget of Rapamycin Complex 1 (TORC1) signaling promotes growth and aging. Inhibition of TORC1 leads to reduced protein translation, which promotes longevity. TORC1-dependent post-transcriptional regulation of protein translation has been well studied, while analogous transcriptional regulation is less understood. Here we screen fission yeast mutants for resistance to Torin1, which inhibits TORC1 and cell growth. Cells lacking the GATA factor Gaf1 (gaf1Δ) grow normally even in high doses of Torin1. The gaf1Δ mutation shortens the chronological lifespan of non-dividing cells and diminishes Torin1-mediated longevity. Expression profiling and genome-wide binding experiments show that upon TORC1 inhibition, Gaf1 directly upregulates genes for small-molecule metabolic pathways and indirectly represses genes for protein translation. Surprisingly, Gaf1 binds to and downregulates the tRNA genes, so it also functions as a transcription factor for RNA polymerase III. Thus, Gaf1 controls the transcription of both protein-coding and tRNA genes to inhibit translation and growth downstream of TORC1.

Highlights

The conserved Target of Rapamycin (TOR) signaling pathway is a key regulator for cellular growth and metabolism in response to nutrients and energy (Gonzalez and Rallis, 2017; Gonzalez and Hall, 2017; Valvezan and Manning, 2019; Wei et al, 2013)
Genes Required for TOR-Mediated Growth Inhibition Target of Rapamycin Complex 1 (TORC1) and TORC2 can be inhibited by Torin1, an ATP analog that blocks cell proliferation in S. pombe (Atkin et al, 2014; Thoreen et al, 2009)
We conclude that Torin1 leads to phenotypes that are diagnostic for TORC1 inhibition

Summary

Introduction

The conserved Target of Rapamycin (TOR) signaling pathway is a key regulator for cellular growth and metabolism in response to nutrients and energy (Gonzalez and Rallis, 2017; Gonzalez and Hall, 2017; Valvezan and Manning, 2019; Wei et al, 2013). Active TORC1 functions on lysosomes, or vacuoles in yeast, in response to growth signals (Binda et al, 2009; Chia et al, 2017; Pou€s and Codogno, 2011; Valbuena et al, 2012). TORC1 promotes aging and shortens lifespan (Gonzalez and Rallis, 2017; Gonzalez and Hall, 2017; Kaeberlein, 2010; Wei et al, 2013). Lifespan is influenced by multiple TORC1-dependent processes, including mitochondrial activity (Hill and Van Remmen, 2014), autophagy (Saxton and Sabatini, 2017), and protein translation (Bjedov and Partridge, 2011; Rallis et al, 2013). Inhibition of S6K can extend lifespan in several organisms (Bjedov et al, 2010; Rallis et al, 2014; Roux et al, 2006; Selman et al, 2009)

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