Website The University of Manchester
Details
The most prominent internal mRNA methylation occurs on adenosine (m6A) and is introduced by a megadalton complex in a conserved RRACH motif. However, additional sequence specificity is required to guide the methylation complex to genuine sites. Deposition of m6A and removal of the m6A complex are regulated process before decoding by YTH reader proteins.
The m6A modification plays a central role in almost every aspect of mRNA processing, in DNA repair, circadian rhythm, neurogenesis and sex determination, among others. Its dysregulation in human is associated with numerous diseases, including metabolic alterations, neuronal disorders and various types of cancers .
Despite recent progress we have a limited understanding how the writer complex is guided to methylation sites and is removed after methylation. Also little is known how m6A mRNA methylation is governed by cellular signalling. Since the m6A demethylase FTO (fat mass and obesity associated) as well as writers and readers are highly expressed in the brain and have been associated with neurological disorders we will focus on the role of the epitransciptome in regulating gene expression in the brain.
Objectives:
1) Determine the targets for the E3 ubiquitin ligase Hak
2) Determine the role of Hak directed ubiquitination in m6A mRNA methylation
3) Determine the role of Hak regulation of the m6A pathway in neuronal gene expression
Project description:
We use a Drosophila genetic model system to investigate m6A mRNA methylation and its regulation using the sex determination pathway. We will identify Hak ubiquitin-ligase targets by proximity labelling, target purification and mass spectrometry. We then will use CRISPR genome engineering to interrogate the role of Hak ubiquitylation for m6A deposition using Drosophila sex determination. Then we will analyse how Hak directed ubiquitination and m6A mRNA methylation will impact on the regulation of selected neuronal genes related to human neurological disease.
Eligibility
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in Molecular Genetics, Structural Biology or a related area. Candidates with experience in Structural Biology, Drosophila genetics or with an interest in mRNA processing are encouraged to apply.
Before you Apply
Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.
How to Apply
To be considered for this project you MUST submit a formal online application form – on the application form select PhD Structural Biology. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester
If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk
Equality, Diversity and Inclusion
Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester
Funding Notes
Applications are invited from self-funded students. This project has a Band 1 (low) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/
References
Bawankar, P., Lence, T., Paolantoni, C., Haussmann, I.U., Kazlauskiene, M., Jacob, D., Heidelberger, J., Richter, F., Nallasivan, M.P., Morin, V., Kreim, N., Beli, P., Helm, M., Jinek, M., Soller*, M. and Roignant*, JY (2021) Hakai is required for stabilizing core components of the m6A mRNA methylation machinery. Nature Communications, 12: 3778.
https://doi.org/10.1038/s41467-021-23892-5
Dix, T., McQuarrie, D.W.J., Brauer, U., Tian Y.W., Haussmann, I. U., Li, M., Futterer, K. and Soller, M. (2026) Multimerization of ELAV in Drosophila is essential for directing neuronal alternative splicing and polyadenylation programs. Genes & Development, in press.
https://doi.org/10.1101/gad.353688.126
Haussmann, I.U., Wu, Y., Nallasivan, M.P., Archer, N., Bodi, Z., Hebenstreit, D., Waddell, S., Fray, R., and Soller, M. (2022) CMTr cap-adjacent 2`-O-ribose mRNA methyltransferases are required for reward learning and mRNA localization to synapses. Nature Communications, 13; 1209.
https://doi.org/10.1038/s41467-022-28549-5
McQuarrie, D.W.J., Bian, W. and Soller, M. (2024). DOA/CLK2 phosphorylates Fl(2)d/WTAP to enhance m6A mRNA methyltransferase activity. BIORXIV/2024/625202
Tian, Y.W., Hadzhiev, Y., Formicola, N., Abis, G., Dodel, M., Alard, E., McQuarrie, D.W.J., Mardakheh, F.K., Conte, S., Pinto-Teixeira, F., Muller, F. and Soller, M. (2026) Larp-DM15/Sgt is a reader for cap-adjacent 2`-O-ribose methylation in ribosomal TOP mRNAs to maintain activity-induced local translation. Preprint. BIORXIV
https://doi.org/10.64898/2026.09.17.752351
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