GTP Depletion and Genome Stability: Mechanistic Insights into Mycophenolic Acid-Induced Transcriptional and DNA Damage Responses
Explore how metabolic stress from mycophenolic acid affects genome stability and transcription. Investigate DNA repair and chromatin changes with direct relevance to cancer and transplant medicine. Employ molecular biology, microscopy, and bioinformatics to uncover novel cellular mechanisms under stress.
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Project Description
Project Overview
Mycophenolic acid (MPA), an immunosuppressant active ingredient prescribed globally, disrupts essential cellular processes beyond immune suppression by depleting GTP. Recent findings indicate MPA impairs RNA polymerase III transcription and induces DNA damage at clinically relevant concentrations, challenging previous assumptions about its selectivity.
What You Will Do
This project aims to define molecular mechanisms linking MPA-induced metabolic stress to transcriptional dysregulation, chromatin architecture, and DNA damage responses. Using human cell lines, you will explore how MPA affects RNA polymerase II and III transcription, causes replication stress, influences DNA repair pathway choice, and compromises chromosome stability. A core focus includes studying MPA modulation of cellular responses to ionising radiation and chemotherapeutic agents.
Techniques involved include molecular and cellular biology methods (RNA-seq, qPCR, ChIP, CRISPR), genome stability assays (γH2AX, 53BP1, micronuclei quantification, EdU incorporation), fluorescence microscopy, and bioinformatic analyses of transcriptomic and genomic data.
Expected Outcomes
The project expects to elucidate how metabolic perturbation by MPA reshapes transcription and DNA repair, enhancing understanding of genome integrity maintenance under metabolic stress. It will also provide insights relevant to improving cancer treatments and transplant patient care by characterizing MPA’s broader cellular effects.
Why This Matters
The work challenges traditional views that MPA selectively targets lymphocytes by blocking GTP synthesis, revealing its wider impact on genome stability and transcriptional regulation. Understanding these mechanisms is critical for refining immunosuppressive therapies and advancing precision medicine approaches in oncology and transplant medicine.
Entry Requirements
How to Apply
Eligibility
Supervisor Profile
Dr Theo Kantidakis is a specialist in transcriptional regulation and chromatin biology, with research focused on how metabolic and molecular stresses impact fundamental cellular processes. He co-supervises this project on MPA’s effects on transcription and genome stability, contributing expertise in molecular biology and gene expression mechanisms.