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

Abstract

Running title: tRNA deregulation during senescence 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. S e n e s c e n c e i s t h e r e f o r e m u c h m o r e 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 YA R S 1 a n d L A R S 1 a m i n o a c y l -t R N A 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 no effect on persistence and the expression of the corresponding tRNA-Cys was not modified. Results also showed that these tRNAs were regulated by mTOR and that this abnormal tRNA biogenesis induced an ER stress which was resolved by the kinase during chemotherapy escape.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 and to chemotherapy resistance.

Aberrant induction of p19Arf-mediated cellular senescence contributes to neurodevelopmental defects

“…Importantly, p19 Arf can directly block tRNA synthesis [ 48 ], while disruption of tRNA function is strongly associated with microcephaly and neurodevelopmental disorders [ 37 , 49 – 53 ]. Interestingly, recent findings also show that induction of senescence involves disruption of tRNA expression, further reinforcing this link [ 54 ]. It will be interesting to determine whether such inhibition of tRNA function contributes to specific, or global alterations in protein translation in senescent cells, either in VPA-induced developmental defects, or other settings.…”

Aberrant induction of p19Arf-mediated cellular senescence contributes to neurodevelopmental defects

“…Interestingly, recent findings also show that induction of senescence involves disruption of tRNA expression, further reinforcing this link (Guillon et al, 2020). It will be interesting to determine whether such inhibition of tRNA function contributes to specific, or global alterations in protein translation in senescent cells, either in VPA-induced developmental defects, or other settings.…”