Investigating mRNA methyl cap regulation, function and therapeutic potential

Victoria Cowling's lab at the University of Dundee investigate how proteins are made in human cells, with the aim of uncovering new approaches to stop the growth of cancer cells and parasites. The human body is made up of trillions of cells with many different functions, e.g. skin, muscle, gut cells. Our health is dependent on these cells responding rapidly to the "instructions" they receive from the body on how to function and whether to grow and multiply, rest or die. In this way, trillions of cells can co-ordinate their activities to form the human body. In cancer, our cells become less responsive to these instructions, and grow and divide in an uncontrolled manner. As a result masses of cells accumulate, often forming cancerous tumours. Cancer researchers investigate why cancer cells become unresponsive to instructions from the body, with the aim of developing new therapies to stop cancer cells growing. Cells are built from proteins and therefore for cells to grow and divide, new proteins need to be made. DNA found in our genes holds the "recipe" for making proteins, but it uses a messenger called RNA to provide precise instructions for proteins. Victoria Cowling's lab is investigating how the RNA messenger is made and handled in the cell, and how it is read to make proteins. Specifically, the Cowling group investigates a structure called the "methyl cap" which flags certain RNAs to be used to make proteins. They discovered that the methyl cap can be influenced by cancer-causing oncogenes and that it is needed for a certain oncogenes to function. Encouraged by these initial results, the Cowling group has initiated a programme of research investigating how the methyl cap is synthesized and regulated in the cell, and how this process goes wrong in cancer cells. They are also collaborating with the Dundee Drug discovery unit to use cutting-edge technology to look for new chemical compounds that stop the methyl cap from forming. Such compounds may form the starting point for developing new anti-cancer therapies. Since human parasites are also dependent on the methyl cap to make protein, Dr Cowling is collaborating with Prof Mike Ferguson at the University of Dundee, to investigate targeting the methyl cap in the parasite, T. brucei, which causes African Sleeping Sickness, a debilitating disease for which treatment remains limited.

We investigate the regulation and function of the mRNA methyl cap with the ultimate aim of developing new families of compounds to inhibit the growth and proliferation of tumour cells and parasites. The methyl cap is a structure added to mRNA during synthesis, marking transcripts for processing and translation initiation. We have made major contributions to the current understanding of the methyl cap. We discovered the first example of methyl cap regulation; c-Myc oncogene upregulates mRNA cap methylation and this is necessary for c-Myc-dependent gene expression and cell proliferation. We discovered an essential activator of the mRNA cap methyltransferase enzyme, RAM.

Fundamental questions remain about how the methyl cap is synthesized, regulated and functions. Answering these questions will have significant impact for our understanding of regulated gene expression, and provide new therapeutic opportunities.
Our objectives:
1 To determine the mechanism by which the methyl cap is synthesised in mammalian cells
2 To determine how cellular signaling pathways regulate the methyl cap, including c-Myc oncogene and CDK-cyclins
3 To determine the function of regulated cap methylation
4 To develop small molecule inhibitors of mRNA cap methylation for use as tools compounds and to investigate their therapeutic potential in both cancer and trypanosome parasites
We will use biochemistry and mass spectrometry to characterize methyl cap synthesis, biophysical techniques including X-ray crystallography to investigate cap methyltransferase structure, transcriptome sequencing and bioinformatics to investigate the function of regulated cap methylation, and the latest screening techniques in collaboration with the Dundee Drug Discovery Unit to identify cap methyltransferase inhibitors. During this fellowship we aim to initiate drug discovery programmes to target tumour cells and trypanosome parasites

We have made fundamental discoveries in medical research which will have impact on other researchers and the public, by many means.

The Nation's health: It is my intention that in the long term, the nation's health benefits from our medical research. Our basic research is investigating how genes are expressed, which will potentially have impact in all areas of medical research in which changes in gene expression cause pathologies. Our basic research may inform and influence other medical research scientists, both in the academic and pharmaceutical sector in the next few months, years or decades. Our more translational research is aimed at cancer cell and parasite growth and proliferation, and if successful is likely to have a significant impact world-wide.

Life Sciences Research, including plant sciences, developmental biology, immunology and neuroscience is likely to be impacted our research. Our discovery that formation of the mRNA methyl cap is regulated is a fundamentally important advance, demonstrating how changes in gene expression result in changes in cellular physiology including growth and proliferation. This impact on other groups research may be occurring right now or in many years time.

The local Dundee community will benefit from our public engagement activities. I host Dundee school children in my lab for 1 day (6 in the last year), with the aim of introducing them to a career in science, and to encourage them to consider going to higher education and university (which most had not). I also take part in the University Open Doors Day, which again informs the local community on what their taxes are being spent, and allows them to ask questions about current cancer research and treatments. I am organising an MRC-PPU open day for cancer patients in 2013, at which they will hear about the research that we do, and how it may progress to new treatments. Hopefully this may provide them with encouragement to stay the course with treatment and to take part in clinical trials.

The drug discovery research community will benefit from the technology used in our research. The methodology and reagents which we are using in the Dundee Drug Discovery Unit, are at the forefront of technology, and therefore likely to benefit the drug discovery community. For example, some of the compound libraries which we are using are made using novel technology and therefore include "unusual" series of compounds. How these compounds behave in various screens will benefit the wider drug discovery community.

The students and postdocs in my lab and college will benefit from the MRC Senior fellowship on many levels. Since they are involved in the cutting edge research, they will gain a broad training in project development and experimental design, effective collaborations, communication with their piers and the wider scientific community, and in publishing papers. They will also receive training in "Generic Skills" that delivers "non-bench" training in skills such as public speaking and public engagement. One of my former postdocs now manages clinical trials, a job which uses the research and organisational skills which she acquired as a postdoc.