UPF1 is a universally conserved RNA helicase in eukaryotes. We recently reported that UPF1 is a mobile protein in all cell compartments and that constantly shuttles between nucleus and cytoplasm, with its intracellular distribution reflecting that of the mRNA, which is characteristically more abundant in the cytoplasm than in the nucleus. Crucially, our observations show that UPF1 associates with nascent pre-mRNA transcripts and that it plays genome-wide roles in nuclear RNA-based processes – including Pol II pausing, mRNA export and most strikingly transcription site retention. These observations radically change our understanding of the roles of UPF1 protein in gene expression and convert UPF1 from a specialised mRNA decay factor to being a global player in mRNA based processes both in the nucleus and in the cytoplasm. The proposed research aims to unveil the specific molecular function(s) that UPF1 performs on ribonucleoprotein (RNP) complexes, and how might these function help to explain why mutations that affect its expression cause disease; and in particular, why even a modest over-expression of UPF1 can restore motoneurons functionality in a rat model of ALS, a deadly neurodegenerative disease for which there is no satisfactory treatment.
Techniques that will be undertaken during the project:
In addition to training in bioinformatics detailed above, thee project will provide advanced training in molecular biology, yeast (or Drosophila) molecular genetics, genomics. The project will involve one or more of the following leading-edge techniques: CRISPR-Cas9 gene editing, NET-seq, ChIP-seq and advanced cell imaging.
Contact: Dr Saverio Brogna, University of Birmingham