A wobbly road to drug resistance in melanoma:
            <scp>tRNA</scp>
            ‐modifying enzymes in translation reprogramming

McMahon, Mary; Ruggero, Davide

doi:10.15252/embj.201899978

Cited by 13 publications

(9 citation statements)

References 12 publications

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“…Collectively, tRNA thiolation appropriately regulates metabolic outputs by controlling phosphate homeostasis, thereby enabling cells to commit to growth (Figure 8). Intriguingly, this correlation of tRNA thiolation with growth and rewired metabolism is emerging in cancer development (McMahon and Ruggero, 2018; Rapino et al, 2018), suggesting possibly conserved metabolic roles for these modified tRNAs.…”

Section: Discussionmentioning

confidence: 98%

A tRNA modification balances carbon and nitrogen metabolism by regulating phosphate homeostasis

Gupta

Walvekar

Liang

et al. 2019

eLife

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Cells must appropriately sense and integrate multiple metabolic resources to commit to proliferation. Here, we report that S. cerevisiae cells regulate carbon and nitrogen metabolic homeostasis through tRNA U34-thiolation. Despite amino acid sufficiency, tRNA-thiolation deficient cells appear amino acid starved. In these cells, carbon flux towards nucleotide synthesis decreases, and trehalose synthesis increases, resulting in a starvation-like metabolic signature. Thiolation mutants have only minor translation defects. However, in these cells phosphate homeostasis genes are strongly down-regulated, resulting in an effectively phosphate-limited state. Reduced phosphate enforces a metabolic switch, where glucose-6-phosphate is routed towards storage carbohydrates. Notably, trehalose synthesis, which releases phosphate and thereby restores phosphate availability, is central to this metabolic rewiring. Thus, cells use thiolated tRNAs to perceive amino acid sufficiency, balance carbon and amino acid metabolic flux and grow optimally, by controlling phosphate availability. These results further biochemically explain how phosphate availability determines a switch to a ‘starvation-state’.

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Section: Discussionmentioning

confidence: 98%

A tRNA modification balances carbon and nitrogen metabolism by regulating phosphate homeostasis

Gupta

Walvekar

Liang

et al. 2019

eLife

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“…Importantly, protein aggregation in the absence of U 34 modification is not limited to the yeast model system but was also observed in nematodes, mice and human cells [27,32,33,70,144,145]. In addition, the absence of the mitochondria-specific taurine-derived wobble uridine modifications induce aggregation of mistargeted mitochondrial proteins [146].…”

Section: A Role Of Protein Aggregation In Neurodegenerationmentioning

confidence: 99%

“…In support of this, it was already demonstrated that a conditional ELP3 knockout in mice induced the unfolded protein response (UPR) and caused reduced numbers of cortical projection neurons, leading to neurodevelopmental defects and microcephaly [144]. While UPR induction in tRNA modification mutants seems to be confined to higher eukaryotic cell systems, aggregation of endogenous cytoplasmic proteins is observed in both mammals and yeast cells [27,32,33,70,144,145,147].…”

Section: A Role Of Protein Aggregation In Neurodegenerationmentioning

confidence: 99%

Roles of Elongator Dependent tRNA Modification Pathways in Neurodegeneration and Cancer

Hawer

Hammermeister

Ravichandran

et al. 2018

Genes

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Transfer RNA (tRNA) is subject to a multitude of posttranscriptional modifications which can profoundly impact its functionality as the essential adaptor molecule in messenger RNA (mRNA) translation. Therefore, dynamic regulation of tRNA modification in response to environmental changes can tune the efficiency of gene expression in concert with the emerging epitranscriptomic mRNA regulators. Several of the tRNA modifications are required to prevent human diseases and are particularly important for proper development and generation of neurons. In addition to the positive role of different tRNA modifications in prevention of neurodegeneration, certain cancer types upregulate tRNA modification genes to sustain cancer cell gene expression and metastasis. Multiple associations of defects in genes encoding subunits of the tRNA modifier complex Elongator with human disease highlight the importance of proper anticodon wobble uridine modifications (xm5U34) for health. Elongator functionality requires communication with accessory proteins and dynamic phosphorylation, providing regulatory control of its function. Here, we summarized recent insights into molecular functions of the complex and the role of Elongator dependent tRNA modification in human disease.

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“…Collectively, our study reveals how tRNA thiolation appropriately regulates metabolic outputs by controlling phosphate homeostasis, thereby enabling cells to commit to growth (Fig 7). Intriguingly, this correlation of tRNA thiolation with growth and rewired metabolism is now emerging in cancer development (McMahon and Ruggero, 2018; Rapino et al , 2018), suggesting possibly conserved metabolic roles for these modified tRNAs.…”

Section: Discussionmentioning

confidence: 99%

A tRNA modification balances carbon and nitrogen metabolism by regulating phosphate homeostasis, to couple metabolism to cell cycle progression.

Gupta

Walvekar

Liang

et al. 2018

Preprint

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10Cells must appropriately sense and integrate multiple metabolic resources to commit to 11 proliferation. Here, we report that cells regulate carbon and nitrogen metabolic homeostasis 12 through tRNA U 34 --thiolation. Despite amino acid sufficiency, tRNA--thiolation deficient cells appear 13 amino acid starved. In these cells, carbon flux towards nucleotide synthesis decreases, and trehalose 14 synthesis increases, resulting in a starvation--like metabolic signature. Thiolation mutants have only 15 minor translation defects. However, these cells exhibit strongly decreased expression of phosphate 16 homeostasis genes, resulting in an effectively phosphate--limited state. Reduced phosphate enforces 17 a metabolic switch, where glucose--6--phosphate is routed towards storage carbohydrates. Notably, 18 trehalose synthesis, which releases phosphate and thereby restores phosphate availability, is central 19 to this metabolic rewiring. Thus, cells use thiolated tRNAs to perceive amino acid sufficiency, and 20 balance carbon and amino acid metabolic flux to maintain metabolic homeostasis, by controlling 21 phosphate availability. These results further biochemically explain how phosphate availability 22 determines a switch to a 'starvation--state'. diverted away from the pentose--phosphate pathway/nucleotide synthesis axis, and towards storage 75 carbohydrates trehalose and glycogen. This thereby alters cellular commitments towards growth 76 and cell cycle progression. Counter--intuitively, we discover that this metabolic--state switch in cells 77 lacking tRNA thiolation is achieved by down--regulating a distant metabolic arm of phosphate 78 homeostasis. We biochemically elucidate how regulating phosphate balance can couple amino acid 79 and carbon utilization towards or away from nucleotide synthesis, and identify trehalose synthesis 80 as the pivotal control point for this metabolic switch. Through these findings we show how tRNA 81 thiol--modifications couple amino acid sensing with overall metabolic homeostasis. We further 82 present a general biochemical explanation for how inorganic phosphate homeostasis regulates 83 commitments to different arms of carbon and nitrogen metabolism, thereby determining how cells 84 commit to a 'growth' or 'starvation' state. 85 86 87 Results 88 89 Amino acid and nucleotide metabolism are decoupled in tRNA thiolation deficient cells 90Earlier studies observed an increased expression of amino acid biosynthetic genes, and an 91 activation of the amino acid starvation responsive transcription factor Gcn4, in cells lacking tRNA 92 thiolation (Laxman et al., 2013; Zinshteyn and Gilbert, 2013; Nedialkova and Leidel, 2015). These 93 studies therefore suggested that tRNA thiolation--deficient cells were amino--acid starved. We 94 investigated this surmise, by directly measuring free intracellular amino acids in wild--type (WT) and 95 tRNA thiolation mutant cells (uba4Δ and ncs2Δ). Note: these two independent pathway mutants 96 were chosen, to avoid misinterpretations coming from possible rol...

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A wobbly road to drug resistance in melanoma: tRNA ‐modifying enzymes in translation reprogramming

Cited by 13 publications

References 12 publications

A tRNA modification balances carbon and nitrogen metabolism by regulating phosphate homeostasis

A tRNA modification balances carbon and nitrogen metabolism by regulating phosphate homeostasis

Roles of Elongator Dependent tRNA Modification Pathways in Neurodegeneration and Cancer

A tRNA modification balances carbon and nitrogen metabolism by regulating phosphate homeostasis, to couple metabolism to cell cycle progression.

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