The increase of life expectancy around the world comes at the unavoidable cost of a rise in the occurrence of neurological diseases such as Parkinson’s as well as debilitating ones like cancer. These conditions prevent the possibility of a sustained quality of life and cost society vast amounts of money for the treatment and care of patients. It is the responsibility of scientists to find innovative methods for treating and eliminating these diseases, allowing for a healthier quality of life. Recently, RNA-binding proteins (RBPs) have been linked to biological processes leading to these diseases as well as the expression of genes relating to obesity. A plethora of natural chemical modifications in RNA fine-tune its structure, allowing for specific interactions which in turn regulate processes such as gene expression and the tuning of translation. Although these have been known for years, their binding proteins have not been systematically studied. The difficulty of the chemical synthesis of modified oligoribonucleotides (ORNs) represents the major bottleneck in this field. The overall aim of this project is to discover RNA-binding proteins which bind to natural, non-canonical modifications which were identified in the messenger RNA (mRNA) of human cancer cell lines.
In order to deepen our understanding of these modifications, these need to be synthesised and then incorporated into oligoribonucleotide strands mimicking natural mRNA. By incubating with cellular extracts, we aim to identify their binding proteins by analysing them using mass spectrometric techniques. This project aims to set the foundation for the better understanding of the mechanisms responsible for the aforementioned conditions, which will in the long term lead to the design of new therapies for their prevention.
During the course of this fellowship, advancements have been made in the design and synthesis of non-canonical RNA modifications. These have been incorporated into nature mimicking RNA strands which have allowed us to identify RBPs directly associated with them. Further investigation into the identity and functionality of these RBPs, in relation to cancer and epigenetic gene expression is necessary to begin unravelling their specific role in nature. Although only preliminary proteomic results have been obtained at the current stage, the tools developed during this fellowship will enable future scientific investigations and hopefully open new directions with respect to therapy development of relevant diseases.
