Dr Victoria Cowling
2007 Principal Investigator, College of Life Sciences, University of Dundee, UK
2015 British Society of Cell Biology Women in Cell Biology Award
2014 EMBO Young Investigator
2013 MRC Senior Fellowship
2011 Lister Institute Prize Fellowship
2007 MRC Career Development Award
2003-2007 Post-doctoral research with Prof. Michael Cole, Dartmouth College, NH, USA and Princeton University, NJ, USA. “Regulation and Function of c-Myc”
1997-2002 PhD Biochemistry with Prof. Julian Downward and Prof. Gerard Evan. Imperial Cancer Research Fund, London, UK. Thesis “Regulation of Caspase Activation during Programmed Cell Death”
1994-1997 Emmanuel College, Cambridge University, UK. B.A. (Hons) Natural Sciences. Part II Zoology
Investigating the regulation and function of the mRNA cap
We investigate the regulation and function of the mRNA cap, and use this information to develop new therapies targeted at inhibiting tumour cell and parasite growth and proliferation.
The methyl cap is a structure found at the 5’ end of transcripts, which marks pre-mRNA for processing and translation initiation. Although it was discovered in the 1970s and characterised in the following years, function studies have been scarce in the last few decades and there are many unanswered questions about mRNA cap function and regulation in the context of our current understanding of gene expression.
Figure 1 mRNA cap. Enzymes which catalyse cap formation are depicted in green
How does the cell regulate formation of the mRNA cap?
Our interest in the mRNA cap began whilst investigating the Myc family of proto-oncogenes, which are deregulated to some extent in most human cancers. Since therapies do not currently exist to inhibit Myc protein function in tumours, there is significant interest in their mode of action. We discovered that Myc proteins upregulate the proportion of transcripts with a “cap-like” structure, correlating with their increased translation. This was a surprising result since cellular regulation of methyl cap synthesis had not been recognised as a mechanism of gene regulation.
Currently we are investigating how mRNA cap formation is regulated during stem cell differentiation, in adaptive immunity and in embryo development. The mRNA cap is emerging as an integrator of cellular signalling information which can drive global and specific changes in gene expression.
How are the mRNA capping enzymes regulated?
We are investigating the basic function of the mRNA capping enzymes because this information is critical for understanding how they are regulated. We identify novel capping enzyme subunits and perform structural, biophysical and biochemical studies to characterise the influence of these subunits on mRNA capping.
We identified the RNMT activating subunit RAM. We are currently investigating how RAM activates RNMT and whether it specifies particular transcripts for enhances methylation. We are also characterising the role of RAM in developmental programmes.
Figure 2 RAM-RNMT
Considering mRNA capping enzymes as therapeutic targets?
We are currently asking whether cancer cells with deregulated gene expression pathways are more sensitive to inhibition of mRNA capping than healthy cells. We have found that particular oncogenes sensitise breast cancer cell lines to inhibition of RNMT. This suggests use of RNMT inhibitors may be most successful therapeutically at treating cancers with these oncogenic mutations.
We are working with the Dundee Drug Discovery Unit to screen for inhibitors of the mRNA capping enzymes. Small molecule inhibitors will be critical to discern the most suitable cancers to treat with mRNA capping inhibitors.
We are working with Mike Ferguson to consider the mRNA capping enzymes as therapeutic targets in T.brucei, the parasite which causes Human African Trypanosomiasis. We are extending this work to other parasites with the Dundee Drug Discovery Unit.
Grasso L, Suska O, Davidson L, Gonatopoulos-Pournatzis T, Williamson R, Wasmus L, Wiedlich S, Peggie M, Stavridis MP, Cowling VH. (2016) mRNA Cap Methylation in Pluripotency and Differentiation. Cell Rep. 2016 Jul 20. pii: S2211-1247(16)30858-0. doi: 10.1016/j.celrep.2016.06.089. [Epub ahead of print] PMID:27452456
Varshney D, Petit AP, Bueren-Calabuig JA, Jansen C, Fletcher DA, Peggie M, Weidlich S, Scullion P, Pisliakov AV, Cowling VH. (2016) Molecular basis of RNA guanine-7 methyltransferase (RNMT) activation by RAM. Nucleic Acids Res. 2016 Jul 15. pii: gkw637. [Epub ahead of print] PMID:27422871
Aregger M, Kaskar A, Fernandez-Sanchez ME, Simone Weidlich S and Cowling VH (2016) CDK1-cyclinB activates RNMT co-ordinating mRNA cap methylation with G1 phase transcription (Mol Cell. 2016 Mar 3;61(5):734-46. doi: 10.1016/j.molcel.2016.02.008.) View Paper
Preston GC, Sinclair LV, Kaskar A, Hukelmann JL, Navarro MN, Ferrero I, MacDonald HR, Cowling VH and Cantrell DA (2015) Single Cell Tuning of Myc Expression by Antigen Receptor Signal Strength and Interleukin 2 in T Lymphocytes EMBO J. 2015 Jul 1. pii: e20149025 View Paper
Cowling VH, Turner S and Cole MD (2014) Burkitt's lymphoma-associated c-Myc mutations converge on a dramatically altered target gene response and implicate ribosome biogenesis in oncogenesis Oncogene. 2014 Jul 3;33(27):3519-27. doi: 10.1038/onc.2013.338. Epub 2013 Sep 9. View Paper
Gonatopoulos-Pournatzis T and Cowling VH (2014) RAM function is dependent on Kapb2–mediated nuclear entry Biochemical J 2013 2014 Feb 1;457(3):473-84. doi: 10.1042/BJ20131359 View Paper
Aregger M and Cowling VH (2013) Human cap methyltransferase (RNMT) N-terminal non-catalytic domain mediates recruitment to transcription initiation sites Biochem J. 2013 Oct 1;455(1):67-73. doi: 10.1042/BJ20130378 View Paper
Gonatopoulos-Pournatzis T, Dunn S, Bounds R, and Cowling VH (2011) RAM/Fam103a1 is required for mRNA cap methylation Molecular Cell 2011 Nov18;44(4):585-596 View Paper
Cowling VH (2010) Enhanced mRNA cao methylation increases Cyclin D1 expression and promotes cell transformation Oncogene. 2010 Feb 11;29(6):930-6. Epub 2009 Nov 16. View Paper
Fernandez-Sanchez ME, Gonatopoulos-Pournatzis T, Preston G, Lawlor MA, and Cowling VH (2009) S-Adenosyl Homocysteine Hydrolase (SAHH) is required for Myc-induced mRNA cap methylation, protein synthesis and cell proliferation Mol Cell Biol 2009, Dec;29(23):6182-91. Epub 2009 Oct 5. View Paper