GTP Depletion and Genome Stability: Mechanistic Insights into Mycophenolic Acid-Induced Transcriptional and DNA Damage Responses

About the Project

Details of the Project

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We have shown that MPA impairs RNA polymerase III transcription1 across multiple human cell types and strikingly, our unpublished data demonstrate that clinically relevant MPA concentrations can directly induce DNA damage.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.

Overseas Applicants

Overseas applicants may apply for this studentship but will need to pay the difference between the ‘Home’ and the ‘Overseas’ tuition fees. Currently the difference between ‘Home’ and the ‘Overseas’ tuition fees is £17,712 for 2026/7. As part of the application, you will be required to confirm that you will provide this additional funding. Please indicate this on the application form in the funding section. This project has associated consumables costs which should be discussed with the supervisor in the first instance and before applying. The supervisor can be contacted at t.kantidakis@aston.ac.uk. When applying, please upload copies of your discussions with the supervisor as confirmation.

Location

This position will be based on the Aston Campus in Birmingham, UK. The successful candidate will need to be located within a reasonable distance of the campus, and will be expected to visit in person regularly.

Person Specification

Candidates should have been awarded, or expect to achieve, EITHER:

a] a First or Upper Second Class award in their undergraduate degree, in a relevant subject.

OR

b] a First or Upper Second Class award in their undergraduate degree, and a Merit or Distinction in a Masters degree, both in a relevant subject.

Qualifications from overseas institutions will be considered, but performance must be equivalent to that described above, and the University reserves the right to ascertain this equivalence according to its own criteria.

Contact information

For formal enquiries about this project contact Dr Theo Kantidakis at t.kantidakis@aston.ac.uk

Submitting an application

We can only consider applications that are complete and have all supporting documents. Applications that do not provide all the relevant documents will be automatically rejected.Your application must include:

1. English language copies of the transcripts and certificates for all your higher education degrees, including any Bachelor degrees.
2. A Research Statement detailing your understanding of the research area, how you would approach the project, and a brief review of relevant literature. Be sure to use the title of the research project you are applying for. There is no set format or word count.
3. A personal statement which outlines any further information which you think is relevant to your application, such as your personal suitability for research, career aspirations, possible future research interests, and further description of relevant employment experience.
4. A Curriculum Vitae (Resume) which details your education and work history.
5. Two academic refereeswho can discuss your suitability for independent research. References must be on headed paper, signed and dated no more than 2 years old. At least one reference should be from your most recent University. You can submit your references at a later date if necessary.
6. Evidence that you meet the English Language requirements. If you do not currently meet the language requirements, you can submit this at a later stage.
7. A copy of your passport. Where relevant, include evidence of settled or pre-settled status.

Interviews

Interviews will be conducted online via Microsoft Teams. If you are shortlisted, you will be contacted directly with details of the interview.

Apply for this position here

Please select “Research - Health Sciences” from the application form options.

If you require further information about the application process please contact the Postgraduate Admissions team at pgr_admissions@aston.ac.uk

Funding Notes

This project covers the Home tuition fees. Candidates who do not have Home status will be responsible for the difference in tuition fees. Currently the difference between ‘Home’ and the ‘Overseas’ tuition fees is £17,712 for 2026/7. This project has associated consumables costs which should be discussed with the supervisor in the first instance and before applying. The supervisor can be contacted at t.kantidakis@aston.ac.uk. When applying, please upload copies of your discussions with the supervisor as confirmation.