Splice Switching Small Molecules as Inducers of Apoptosis

Background - No other biomacromolecule has such a wide-ranging role in biological processes as RNA, yet these roles remain poorly understood. The most compelling yet complex example of this is alternative mRNA splicing. This biological process cuts large portions of pre-mRNA and rearranges the remaining sequences to form a mature mRNA molecule. Alternative RNA splicing is essential to the regular functioning of eukaryotic cells and misregulation of this process results in the onset of up to 15 % of all cancers.

Challenge – This studentship aims to elucidate the critical molecular interactions that the cell uses to regulate this process. To realise this vital goal, the field requires molecular tools and assays that can be used to identify key structural changes in the regulation of splicing.

The project - The candidate will prepare a suite of small molecule probes and non-natural nucleotides by chemical synthesis and develop new methodology for their site-specific incorporation into RNA molecules. These non-natural nucleotides will bear chemical handles which will be used as tagging sites for the attachment of fluorophores for single molecule studies in collaboration with Prof. Ian Eperon (Department of Biochemistry, University of Leicester). The candidate will then apply this methodology to study the splicing profile of the known oncogene BCL-x and determine the key molecular characteristics for its mis-regulation in tumours. This splicing assay will also be used to screen for splice switching potential of small molecules to induce the pro-apoptotic splicing isoform of Bcl-x.

Throughout the project the candidate will benefit from close interactions and collaboration with leading scientists in the area of RNA splicing (Prof. Ian Eperon, Leicester; Prof. Hing Leung, Beatson Institute for Cancer Research) and you will receive extensive training in all aspects of chemical synthesis, nucleic acid and protein chemistry, and biochemical assays required for the project. You will also interact with synthetic organic chemists and chemical biologists as part of the EPSRC/GSK doctoral training centre based in Strathclyde.

Keywords: Synthetic organic chemistry; Synthetic Biology; Chemical Biology; nucleic acid chemistry; gene regulation; cancer