Mycophenolic acid (MPA), the active ingredient of the immunosuppressant mycophenolate mofetil, is prescribed to millions worldwide, yet we lack a fundamental understanding of how it works. Traditionally viewed as acting selectively on lymphocytes by blocking de novo GTP synthesis, emerging evidence, including our own, reveals that GTP depletion disrupts essential cellular processes far beyond immune suppression.
We have shown that MPA impairs RNA polymerase III transcription1 across multiple human cell types and strikingly, our unpublished data demonstrate that clinically relevant MPA concentrations can directly induce DNA damage. These findings challenge long-held assumptions about MPA’s selectivity and raise critical mechanistic questions: How does metabolic stress from GTP depletion reshape transcriptional programmes and DNA repair pathways? What are the consequences of prolonged MPA exposure for genome integrity in human cells?
This PhD project will define the molecular mechanisms linking MPA-induced metabolic stress to transcriptional dysregulation, chromatin architecture and DNA damage responses. Using a panel of human cell lines, you will investigate how MPA affects RNA polymerase II and III transcription, triggers replication stress, alters DNA repair pathway choice and compromises chromosomal stability. A key component will be determining how MPA modulates cellular responses to ionising radiation and chemotherapeutic DNA-damaging agents—findings with direct relevance to cancer therapy and transplant medicine.
Methods will span molecular and cellular biology (RNA-seq, qPCR, ChIP, CRISPR), genome stability assays (γH2AX, 53BP1, micronuclei quantification, EdU incorporation) and fluorescence microscopy, complemented by bioinformatic analysis of transcriptomic and genomic datasets.
Co-supervised by experts in transcriptional regulation (Kantidakis) and DNA damage repair (Kysela), this project offers rigorous training in mechanistic molecular biology, chromatin biology and genome stability research. It is ideal for students interested in understanding how metabolic perturbations reshape cellular physiology, with direct relevance to cancer biology, pharmacology and precision medicine.
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.
