University of Dundee

EASTBIO: Investigating therapeutic targeting of the mRNA cap methyltransferases

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership This opportunity is open to UK and EU nationals.

Applicants should apply by completing the EASTBIO application form (downloadable from the EASTBIO website) and e-mail to Candidates should also include their academic transcripts and ensure that they ask their referees to send completed references to Applicants may wish to explain their motivation for joining the EASTBIO training programme.

The mRNA cap recruits processing factors to pre-mRNA, which are required for the production of mature mRNA and translation. Formation of the mRNA cap is regulated by oncogenes, immune signalling pathways and developmental pathways, resulting in changes in gene expression, cell function and fate. We are interested in how the mRNA capping process could be targeted in therapeutic scenarios, for example to inhibit oncogenic pathways and cell proliferation, to redirect immunological signalling and to direct cellular programming. The PhD project will investigate how repressing the enzymes which catalyse mRNA cap formation impacts on gene expression, cell function, cell proliferation and cell fate. The mRNA capping enzymes will be inhibited or deleted using the latest molecular biology techniques in cancercell lines, embryonic stem cells and T cells. The impact of mRNA capping enzyme deletion on gene expression will be determined using the latest next generation sequencing and proteomics technologies. Cell-based assays will be used to determine the role of capping enzyme function on cell physiology and proliferation. The project will be performed in the laboratory of Prof Victoria Cowling, in the Centre for Gene Regulation, School of Life Sciences, University of Dundee.

The Cowling lab is funded by grants from UK and European governments and has abundant postdoctoral expertise to support the student. The major advantage of the project is that it is collaborative with Prof David Gray of the Dundee Drug Discovery Unit, University of Dundee. Prof Gray’s and Cowling’s teams have a long standing collaboration to develop inhibitors of the mRNA capping enzymes. A key component of the research project is to characterise the impact of capping enzyme inhibitors in cells. The Dundee Drug Discovery Unit is a world class facility with expertise in all aspects of compound development and drug discovery.

Dunn S, Lombardi O and Cowling VH (2019) Oncogenic PIK3CA mutations increase dependency on the mRNA cap methyltransferase, RNMT, in breast cancer cells Open Biology 2019 Apr 26;9(4):190052. doi: 10.1098/rsob.190052.PMID:30991934

Galloway A and Cowling VH(2018) mRNA cap regulation in mammalian cell function and fate BBA Gene regulation Mechanisms Oct 9. pii: S1874-9399(18)30167-6. doi:10.1016/j.bbagrm.2018.09.011 PMID: 30312682

Jantsch M, Quattrone A, O’Connell M, ...Cowling al (2018) Positioning Europe for the EPITRANSCRIPTOMICS Challenge RNA Biology ;15(6):829-831. doi:10.1080/15476286.2018.1460996. Epub 2018 May 9. PMID:29671387