부산대학교 도서관

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 proliferative arrest 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 up-regulated. Reducing tRNA transcription appears necessary to control the strength of senescence since RNA pol III inhibition through BRF1 depletion maintained senescence and blocked the generation of escaping cells. mTOR inhibition also prevented chemotherapy-induced senescence 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, results showed that their corresponding tRNA ligases, LARS and YARS, were necessary for senescence escape. This effect was specific since the CARS ligase had no effect on persistence. By contrast, the down-regulation of LARS and YARS reduced the emergence of persistent cells and this was associated with the modulation of E2F1 target genes expression. 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 tumor suppressive pathway. Author summary: Senescence is a tumor suppressive mechanism induced in response to oncogenes or chemotherapy. Senescence was initially defined as a definitive arrest of cell proliferation but doubts have emerged as to the value of this mechanism in terms of suppression. Recent findings published by several laboratories including our own have shown that some cells escape senescence to become more transformed. This study shows that different tRNAs are expressed in growing, senescent or emerging cells. The tRNA-Leu-CAA and tRNA-Tyr-GTA are up-regulated during senescence escape whereas this was not the case of the other tRNAs tested. In addition, using proteomic analysis and inactivation experiments, we found that the corresponding tRNA ligases, YARS for tRNA-Tyr-GTA and LARS for the tRNA-Leu-CAA, are necessary for senescence escape. Results also show that the expression of the tRNA-Leu-CAA and tRNA-Tyr-GTA are controlled by the mTOR pathway and that this kinase is necessary for senescence escape. Reducing tRNA transcription appears necessary to control the strength of senescence since RNA pol III inhibition maintained senescence and blocked the generation of escaping cells. In light of these results, we propose the hypothesis that the heterogeneity of tRNAs and ligases expression leads to distinct states of light or deep senescence. [ABSTRACT FROM AUTHOR]