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TRNA Biogenesis and Specific Aminoacyl-tRNA Synthetases Regulate Senescence Stability Under the Control of mTOR

ABSTRACT: Oncogenes or chemotherapy treatments trigger the induction of suppressive pathways such as apoptosis or senescence. Senescence was initially defined as a definitive arrest of cell proliferation but recent results have shown that this mechanism is also associated with cancer progression and chemotherapy resistance. Senescence is therefore much more heterogeneous than initially thought. How this response varies is not really understood, it has been proposed that its outcome relies on the secretome of senescent cells and on the maintenance of their epigenetic marks. Using experimental models of senescence escape, we now described that the stability of this suppression relies on specific tRNAs and aminoacyl-tRNA synthetases. Following chemotherapy treatment, the DNA binding of the type III RNA polymerase was reduced to prevent tRNA transcription and induce a complete cell cycle arrest. By contrast, during senescence escape, specific tRNAs such as tRNA-Leu-CAA and tRNA-Tyr-GTA were upregulated. Reducing tRNA transcription appears necessary to control the strength of senescence since RNA pol III inhibition through BRF1 depletion maintained senescence and blocked cell persistence. mTOR inhibition also prevented CIS escape in association with a reduction of tRNA-Leu-CAA and tRNA-Tyr-GTA expression. Further confirming the role of the tRNA-Leu-CAA and tRNA-Tyr-GTA, their corresponding tRNA ligases, YARS and LARS, were necessary for senescence escape. This effect was specific since the CARS ligase had no effect on persistence. YARS and LARS inactivation reduced cell emergence and proteomic analysis indicated that this effect was associated with the down-regulation of E2F1 target genes. Overall, these findings highlight a new regulation of tRNA biology during senescence and suggest that specific tRNAs and ligases contribute to the strength and heterogeneity of this suppression. !

INSTRUMENT(S): TripleTOF 5600

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: Catherine Guette

LAB HEAD: Olivier Coqueret

PROVIDER: PXD029535 | Pride | 2021-12-09

REPOSITORIES: Pride

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Project description:Skeletal muscle atrophy is dictated by the balance between protein synthesis and protein breakdown, known as proteostasis. With advanced age, muscle atrophy contributes to development of co-morbidities, loss of strength and independence, and all-cause mortality. Aging also coincides with the accumulation of senescent cells within skeletal muscle that produce inflammatory products, known as the senescence associated secretory phenotype. Previously, we found that a metformin + leucine (MET+LEU) combination treatment had synergistic effects in aged mice to improve skeletal muscle structure and function during disuse atrophy. Therefore, the objective of this study was to determine the mechanisms by which MET+LEU exhibits muscle atrophy protection in vitro and if this occurs through cellular senescence. C2C12 myoblasts differentiated into myotubes were used to determine MET+LEU mechanisms during serum-deprivation (SD) atrophy. Single myofibers were isolated from aged (22-23 mo) C57Bl6/J mice, and human primary myoblasts were extracted from a healthy older adult donor. 25 + 125 µM MET+LEU treatment increased differentiation of myotubes and prevented SD induced atrophy. Low concentration (0.1 + 0.5 µM) MET+LEU had unique effects to prevent myotube atrophy and cause transcriptional reprogramming compared to individual therapies. SD increased inflammatory and cellular senescence pathways that was reversed with MET+LEU treatment. SD resulted in dysregulated proteostasis that was rescued with MET+LEU, and proteasome inhibition with MG-132 also rescued myotube atrophy. Cellular senescence transcriptional pathways and markers increased by SD were reversed with MET+LEU treatment, and dasatinib + quercetin (D+Q) senolytic treatment prevented myotube atrophy similar to MET+LEU. In aged myofibers, MET+LEU prevented SD atrophy, and in human primary myotubes MET+LEU prevented reductions in myonuclei fusion. These data provide evidence that MET+LEU has muscle cell intrinsic properties to prevent atrophy by reversing senescence and improving proteostasis

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TRNA Biogenesis and Specific Aminoacyl-tRNA Synthetases Regulate Senescence Stability Under the Control of mTOR

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