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

Abstract

Target 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 (gaf1D) grow normally even in high doses of Torin1. The gaf1D 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.

Novel Links between TORC1 and Traditional Non-Coding RNA, tRNA

“…In S. pombe , the downregulation of TORC1 upon nutrient starvation causes the activation of the GATA transcription factor Gaf1 [ 74 ]. Recently, Gaf1 has been shown to bind tRNA genes and repress their transcription, thereby leading to the extension of the chronological lifespan [ 75 ].…”

The Target of Rapamycin Signalling Pathway in Ageing and Lifespan Regulation

“…Upregulated genes in gaf1 mutant cells grown in nitrogen-rich medium are enriched in nitrogen starvation-responsive genes Ste11 targets [ 54 ]. While budding yeast GATA transcription factors are not directly implicated in lifespan regulation, a recent study [ 18 ] indicated that, similarly to the C. elegans elt-2 , the fission yeast gaf1 is an anti-ageing gene. Cells lacking gaf1 are short-lived and Gaf1 is partially required for Torin1-induced lifespan extension [ 18 ].…”

“…Firstly, via direct phosphorylation of the translation regulators eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) [ 7 , 8 ] and ribosomal protein S6 kinase 1 (S6K1) [ 9 , 10 , 11 , 12 , 13 ]. Secondly, through regulation of transcription (dependent on all three RNA polymerases) of genes coding for ribosomal proteins [ 1 , 9 , 14 ], ribosome biogenesis factors [ 15 ] and tRNAs [ 16 , 17 , 18 , 19 , 20 ]. Apart from translation-related genes TORC1 has major positive impact on gene expression related to growth and metabolism [ 2 , 18 ] and a negative action on genes coding for proteins related to cellular stress [ 21 , 22 , 23 ].…”

“…Secondly, through regulation of transcription (dependent on all three RNA polymerases) of genes coding for ribosomal proteins [ 1 , 9 , 14 ], ribosome biogenesis factors [ 15 ] and tRNAs [ 16 , 17 , 18 , 19 , 20 ]. Apart from translation-related genes TORC1 has major positive impact on gene expression related to growth and metabolism [ 2 , 18 ] and a negative action on genes coding for proteins related to cellular stress [ 21 , 22 , 23 ]. Genetic or pharmacological inhibition of mTOR activity stimulates autophagy, a conserved lysosomal catabolic pathway controlling the degradation and turnover of macromolecules and organelles and maintaining metabolic homeostasis at both the cellular and whole-organism level [ 24 , 25 ].…”

“…Rapamycin directly binds FKBP12 and the complex then binds and inhibits the TOR kinase [ 37 ] with beneficial effects on both health span and lifespan of all cellular and organismal systems tested [ 5 ]. Intense research, so far, has shown that genetic or pharmacological interventions that lower mTOR activity result in upregulation of stress responses, alteration of mitochondrial respiration and metabolism, slower ageing rates and prolongment of lifespan [ 5 , 18 , 22 , 25 , 38 , 39 ]. In this review, we briefly present a snapshot of roles of the mTOR pathway in ageing and lifespan regulation, focusing on four basic cellular processes: gene transcription, protein translation, autophagy and metabolism presenting specific examples.…”