Mycophenolic acid (MPA) is the active ingredient of mycophenolate mofetil, a broadly used immunosuppressant, recommended for the treatment of autoimmune diseases and to avoid organ rejection in transplantations. MPA is a specific and potent inhibitor of the inosine monophosphate dehydrogenase enzyme, preventing the de novo synthesis of GTP.
Although it is generally believed that MPA only, or at least mainly, affects B and T lymphocytes, which singularly depend on the de novo pathway for GTP synthesis, we have shown that MPA-mediated GTP depletion affects the gene expression of RNA polymerase III in different cell types1. Furthermore, we now have preliminary data that MPA can result in DNA damage in several cell types, even when used in clinically relevant concentrations.
In this project we will investigate the cellular and molecular mechanisms through which MPA treatment can impact gene expression and DNA repair, result in DNA damage and affect cell survival. We will use different human cell lines and examine the adverse effects of ionising radiation and chemotherapeutic DNA damage drugs, that mimic cancer treatments at the cellular level, on cells treated with MPA.
We will employ a broad range of standard and cutting edge cellular, molecular, biochemical and bioinformatic techniques that include, among others, RNA-Seq and qPCRs, protein and chromatin assays, immunofluorescence microscopy, DNA damage and repair, and genomic instability assays.
The Kantidakis lab is a research-active lab, suitable for enthusiastic and highly motivated PhD candidates. The successful candidate will benefit from working alongside the principal investigator, who will provide direct mentorship and training.
References
1. Jurkiewicz, A., Leśniewska, E., Cieśla, M., Gorjão, N., Kantidakis, T., White, R.J., Boguta, M., and Graczyk, D. (2020). Inhibition of tRNA Gene Transcription by the Immunosuppressant Mycophenolic Acid. Mol Cell Biol 40, e00294-19. 10.1128/MCB.00294-19.
