Eukaryotic RNA biology: understanding the role that the RNA helicase UPF1 plays in gene expression

UPF1 is an RNA helicase that is conserved in all eukaryotes and it is best known for its role in nonsense-mediated mRNA decay (NMD). NMD is believed to be a cellular quality control mechanism of gene expression that detects mRNAs carrying a premature translation termination codon and triggers their rapid degradation. NMD is a major determinant of gene expression, shapes transcriptomes and is a promising drug target. Most promising, UPF1 is a candidate drug for amyotrophic lateral sclerosis (ALS) as there is evidence that expression of human UPF1 restores motor function in a rat model of ALS (Jackson et al., 2015). However, neither NMD nor the general role that UPF1 plays in gene expression is understood in any organism (Brogna et al., 2016; Brogna and Wen, 2009). This project aims to understand what functions other than NMD UPF1 plays in the cell, particularly: pre-mRNA processing and translation. We are interested to know whether these other functions of UPF1 can better than NMD explain why increasing its level in neurons restores ALS paralysis in animal models of this disease. We anticipate that our research should therefore not only improve our basic understanding of the mechanisms by which proteins like UPF1 regulate gene expression but also contribute knowledge relevant to its future biomedical and biotechnological exploitation. Whilst the PhD project will follow this general research plan/strategy, it will focus on a specific question, which will be defined at the start, to match interest and aptitude of the student with the state of the field at the time.