University of Dundee

Dr Victoria Cowling

Investigating the synthesis, function and therapeutic potential of the mRNA methyl cap
Position: 
Lister Institute Fellow and MRC Senior Fellow
Address: 
College of Life Sciences, University of Dundee, Dundee
Full Telephone: 
+44 (0) 1382 386997, int ext 86997
Email: 

Biography

  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

Research

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.

 

Publications

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.)

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

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.

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

Preston GC, Feijoo-Carnero C, Schurch N, Cowling VH and Cantrell DA  (2013) The impact of KLF2 modulation on the transcriptional program and function of CD8 T cells PLoS One. 2013 Oct 14;8(10):e77537

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

E2F1-dependent methyl cap formation requires RNA pol II phosphorylation (2012) Aregger M and Cowling VH Cell Cycle 2012 Jun1;11(11) 2146-8

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

Cowling VH (2010) Enhanced mRNA cap methylation increases Cyclin D1 expression and promotes cell transformation  Oncogene. 2010 Feb 11;29(6):930-6. Epub 2009 Nov 16.

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.

Cole MD and Cowling VH (2009) Specific regulation of mRNA cap methylation by the c-Myc and E2F1 transcription factors Oncogene 2009 Mar 5;28(9):1169-75. Epub 2009 Jan 12.