May 2, 2020

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

BioRxiv : the Preprint Server for Biology
J. GuillonOlivier Coqueret

Abstract

Senescence normally prevents the propagation of abnormal cells but is also associated with cancer progression and chemotherapy resistance. These contradictory effects are related to the stability of epigenetic marks and to the senescence-associated secretory phenotype (SASP). The SASP reinforces the proliferative arrest but also induces tumor growth and inflammation during aging. Senescence is therefore much more heterogeneous than initially thought. How this response varies is not really understood. Using experimental models of senescence escape, we now described that the deregulation of tRNA biogenesis affects the stability of this suppression, leading to chemotherapy resistance. Proteomic analyses showed that several aminoacyl-tRNA synthetases were down-regulated in senescent cells. tRNA transcription was also inhibited as a consequence of a reduced DNA binding of the type III RNA polymerase. Reducing RNA Pol III activity by BRF1 depletion maintained senescence and blocked cell persistence. Results showed that the YARS1 and LARS1 aminoacyl-tRNA synthetases were necessary for cell emergence and that their corresponding tRNA-Leu-CAA and tRNA-Tyr-GTA were up-regulated in persistent cells. On the contrary, the CARS1 ligase had n...Continue Reading

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Mentioned in this Paper

Genome
Malignant Neoplasm of Stomach
Interphase
Blade - plant part
Spatial Distribution
Chromosomes, Human
KLF6 wt Allele
Evaluation
Genomics
Subintima

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