Victoria Cowling

Investigating the regulation, function and therapeutic potential of the mRNA cap

We investigate how the body controls which proteins are made in its cells. We use this knowledge to design therapeutic approaches to starve cancer cells.

Human cells contain about 25000 protein-encoding genes which are continually controlled to ensure expression at the right time and place.  Our focus is to understand how cells control and co-ordinate gene expression using a modification of mRNA called the mRNA cap.  The mRNA cap structure protects transcripts from degradation and recruits factors which drive RNA processing events.  We have found that different signals which the cell encounters (developmental, immunological, oncogenic) can alter the rate and extent to which the mRNA cap forms, either across the transcriptome or on specific transcripts.  Thus the mRNA cap is an integrator of cellular signalling information, which directs reshaping of the cellular proteome in response to external and internal signals.

The mRNA cap describes a collection of structures which form on the 5’ end of RNA pol II transcripts.   Capping enzymes catalyse modification of the first few nucleotides to form the cap.  Most of these capping enzymes are recruited to phosphorylated RNA pol II at the early stages of transcription, thus capping the transcript as it is being synthesised.  Our research investigates how the capping enzymes function biochemically and how they influence gene expression in cancer cells, embryonic stem cells and primary T cells.  We look at how cellular signalling pathways influence the expression or activity of the capping enzymes to change gene expression, cell function and cell physiology. We are working with the Dundee Drug Discovery Unit to develop inhibitors of the mRNA capping enzymes.