An mRNA contains instructions not only for what protein is made, but also how that protein assembles inside the cell. Understanding this regulatory information is critical for the safe and effective development of mRNA therapeutics for protein replacement therapies. These therapies use synthetic mRNAs to instruct cells to produce functional proteins that are otherwise defective in monogenic diseases.
For these therapies to be effective, the encoded protein must fold correctly, form the appropriate complexes and reach the correct cellular location. For proteins that interact with their partners co-translationally (during their synthesis on the ribosome), appropriate control of ribosome movement will likely be critical to ensure interacting subunits find each other at the right time. Yet how this process is regulated remains unclear.
Therapeutic mRNAs differ from endogenous mRNAs in several important ways. For example, they incorporate modified nucleotides to reduce innate immune activation, which may also influence the dynamics of ribosome movement and co-translational assembly. In addition, synthetic mRNAs are delivered directly to the cytoplasm and bypass the nucleus. Whether features normally acquired during an mRNA’s nuclear history influence these processes remains unexplored.
This studentship will investigate how co-translational processes differ between synthetic and endogenous mRNAs. Using a reporter assay developed in the Waldron lab to quantify co-translational assembly, single-molecule live-cell imaging to track RNA localisation and ribosome profiling to measure ribosome dynamics, the student will determine how therapeutic mRNA modifications and an mRNAs nuclear history influence protein function.
The student will be embedded within an ambitious and supportive research team funded through a Wellcome CDA, providing an exciting and collaborative environment in which to develop expertise in molecular biology, quantitative imaging and bioinformatics.
