The YARS Tyrosyl tRNA Synthetase Regulates Senescence Induction and Escape Through the Transcriptional Control of LIN9, a Member of the DREAM Complex

Senescence is a tumor suppressor mechanism triggered by oncogene expression and chemotherapy treatment. It orchestrates a definitive cessation of cell proliferation through the activation of the p53-p21 and p16-Rb pathways, coupled with the compaction of proliferative genes within heterochromatin regions. Some cancer cells have the ability to elude this proliferative arrest but the signaling pathways involved in circumventing senescence remain to be characterized. We have recently described that malignant cells capable of evading senescence have an increased expression of specific tRNAs, such as tRNA-Leu-CAA and tRNA-Tyr-GTA, alongside the activation of their corresponding tRNA ligases, namely LARS and YARS. We have previously shown that YARS promotes senescence escape by activating proliferation and cell cycle genes but its functions during this proliferative arrest remain largely unknown. In this study, we have continued to characterize the functions of YARS, describing non-canonical transcriptional functions of the ligase. Our results show that YARS is present in the nucleus of growing and senescent cells and interacts with the Trim28 transcriptional regulator. Importantly, YARS binds to the LIN9 promoter, a critical member of the Dream complex responsible for regulating cell cycle transcription. YARS facilitates the binding and the phosphorylation of the type II RNA polymerase and promotes the deposit of activating epigenetic marks on the LIN9 promoter. Consequently, during senescence escape, YARS promotes LIN9 expression and both proteins are necessary to induce the proliferation of emergent cells. These results underscore the unconventional transcriptional functions of YARS in promoting senescence escape by activating LIN9 and likely influencing the functions of the Dream complex.