tRNA biogenesis and specific aminoacyl-tRNA synthetases regulate senescence stability under the control of mTOR

PLoS Genet. 2021 Dec 20;17(12):e1009953. doi: 10.1371/journal.pgen.1009953. eCollection 2021 Dec.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acyl-tRNA Synthetases / genetics*
  • Apoptosis / genetics
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Cycle Checkpoints / genetics
  • Cell Proliferation / genetics
  • Cellular Senescence / genetics*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • E2F1 Transcription Factor / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • MCF-7 Cells
  • RNA Polymerase III / genetics
  • RNA, Transfer / biosynthesis
  • RNA, Transfer / genetics
  • TATA-Binding Protein Associated Factors / genetics*
  • TOR Serine-Threonine Kinases / genetics*
  • Transcription, Genetic / genetics

Substances

  • BRF1 protein, human
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • TATA-Binding Protein Associated Factors
  • RNA, Transfer
  • TOR Serine-Threonine Kinases
  • RNA Polymerase III
  • Amino Acyl-tRNA Synthetases

Grants and funding

This work was supported by grants from the Ligue Contre le Cancer (to OC, Comité du Maine et Loire, du Finistère), the Rotary Club (to JG, Maine et Loire) and the SIRIC ILIAD Nantes-Angers-INCA-DGOS-Inserm grant 12558 (to OC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.