Post-transcriptional control of gene expression following toxic injury

Protein synthesis is the process by which the information in the genetic material in the cell, DNA is converted via an intermediary substrate called mRNA, into proteins. For proteins to be made the mRNA must interact with a large complex called the ribosome which consists of RNAs and proteins. Ribosomes can therefore be thought of as “molecular factories” that make proteins. They do this by decoding the genetic information that is held in the mRNA and bringing all the building blocks together to synthesise proteins. The rate at which proteins are made is very highly regulated and cells respond to alterations in the external environment, such as exposure to toxic chemicals and chemotherapeutic agents by modifying both the rate at which they make proteins and importantly the types of proteins that they make. We are studying these processes to gain a greater understanding of the cells/organisms response to toxic insult.

This proposal is built around the hypothesis that post-transcriptional control of gene expression is essential to dictate cell fate in response to toxic insult initiated by a wide range of external and internal challenges. The detailed mechanistic information on post-transcriptional responses generated from our research will be used to explore, understand and predict:
i) The toxicity associated with exposure to environmental agents.
ii) The “on” and “off” target toxicity of chemotherapeutic agents, in particular the exciting, emerging drugs which target the canonical protein synthesis machinery and associated RNA binding proteins.
iii) The off target effects of new RNA-based therapeutics, particularly modified in vitro mRNAs (IVTmRNAs) and devise novel ways (e.g. through codon composition changes) to limit their toxicity.
This research is novel and timely. The data generated from these studies will populate adverse outcome/toxicity pathways, utilised by a wide-range of stakeholders, and through collaboration with our industrial partners, facilitate the transfer of RNA-based biologics into the clinic.