Gene-specific control of tRNA expression
Transfer RNAs (tRNAs) are small adaptor RNAs that need to be expressed in a balanced manner to safeguard their roles in correctly decoding mRNA sequences into proteins. These molecules, transcribed at high rates by RNA Polymerase III (Pol III), were initially considered constitutively expressed. However, it recently emerged that tRNAs are selectively regulated to favor the translation of key proteins driving cellular processes such as proliferation or differentiation. Yet, the molecular players involved in the regulation of individual tRNA genes remained unknown.
Transformed cells were shown to alter the expression of specific tRNAs to match the codon bias found in proteins supporting their proliferation or survival. Thus, we aim to uncover the mechanisms and functions of the gene-specific control of tRNA expression during cell growth and adaptation to the environment, such as hypoxia, which are both hallmarks of cancer. To achieve this ambitious goal, this research line investigates the coupling of signaling events to the regulation of specific tRNA genes and their function in cancer cell proliferation/survival or differentiation. We aim to identify signaling pathways, novel transcriptional regulator and Pol III-dependent genes selectively used by cancer cells to support their proliferation. By advancing our understanding of tRNA gene regulation, we hope to uncover new targets for drug development and enable the establishment of new diagnostic tools.
Precision targeting of aminoacyl-tRNA-synthetase in cancer
To function in translation, tRNAs need to be loaded with their corresponding amino acid, a step catalyzed by 20 aminoacyl-tRNA-synthetases (ARS). In contrast to normal cells, hyperproliferative cancer cells require higher protein synthesis. In this project, we aim to evaluate whether (t)RNA profiling coupled with the functional screening of ARS usage in a panel of glioblastoma (GBM) cells could guide the selection of inhibitors for the specific and precise targeting of these cancer cells compared to normal normal cells. We aim to uncover the basic rules and mechanisms used by GBMs to support their proliferation/survival via a tumor-specific translational program and to evaluate the efficiency of precision targeting of ARS enzymes in impairing cancer cell growth.