Eukaryotic gene expression: understanding the role of UPF1 in global mRNA processing and amyotrophic lateral sclerosis (ALS)

UPF1 is an RNA helicase commonly discussed for its cytoplasmic roles in modulating nonsense-mediated mRNA decay (NMD). NMD is a quality control mechanism which enables the detection and degradation of aberrant mRNAs. NMD is of particular interest for drug targeting, as it involves many steps of mRNA regulation. Strikingly, 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, the functional roles of UPF1 remain inconclusive. Recent evidence shows that UPF1 functions in the nuclei of Drosophila, where it associates with active genes allowing for appropriate mRNA packaging and export (Singh et al., 2019). Despite this, UPF1 recruitment to nascent mRNAs and its nuclear roles remain poorly understood. Such roles are crucial to uncover for the appropriate understanding of how UPF1 can be used as a drug target in neurodegenerative diseases.
This project combines wet and dry-lab procedures to address the roles of UPF1 on global mRNA processing. Evidence shows that in UPF1 depleted conditions, nuclear aggregates form, meaning this protein is required for transcriptome homeostasis (Singh et al., 2019). Thus, techniques including RNA-seq, ChIP-seq and SLAM-seq will show how UPF1 interacts and affects pre-mRNAs exploring its association with nascent transcripts and its roles in their appropriate splicing, packaging and export.