Prof Martin Bushell - RNA and Translational Control in Cancer

Introduction

Bushell head 115

The dysregulation of protein synthesis in the tumour clone and the supporting stroma is essential for the delivery of oncogenic gene programmes that allow the establishment of both the intracellular and extracellular environments. This is driven by two fundamental post-transcriptional processes. First, hyperactivation of the eIF4F translation initiation complex results in the specific upregulation of oncogenic mRNAs. Secondly, a fundamental shift within tRNA pools promotes oncogenic gene expression programmes by altering the protein synthesis landscape. Recent data from our group and others show that these two processes are coordinated by a number of distinct regulatory RNA-binding complexes and suggest that there is cross-talk between these key steps of the translation process. Our current hypothesis is that these complexes control and connect all post-transcriptional stages of the mRNA lifecycle, from selection, through decoding, to turnover.

The balance of expressed tRNA and codon usage of oncogenic mRNAs that are sensed by these complexes represent a targetable axis of the malignant phenotype, which could be explored therapeutically if mechanistic understanding was available.

The research in our laboratory focuses on understanding how RNA-binding protein complexes, tRNA abundance and codon optimality dictate oncogenic protein production in a coordinated manner. We employ biochemical, biophysical and computational methods to address these questions. We are interested in how the changing tumour environment results in the redeployment of mRNA-binding complexes that control the balance between upregulation of protein translation and mRNA turnover and translational silencing. These mechanistic insights drive our endeavours in designing assays and drug discovery pipelines to target the heart of tumour cell biology.