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Understanding the role that the RNA helicase UPF1 plays in transcription and RNA processing

Primary Supervisor: Dr Saverio Brogna, School of Biosciences

Secondary supervisor: Dr Yun Fan

PhD project title: Understanding the role that the RNA helicase UPF1 plays in transcription and RNA processing

University of Registration: University of Birmingham

Project outline:

UPF1 is an RNA helicase conserved in all eukaryotes best known for its cytoplasmic role in nonsense-mediated mRNA decay (NMD). NMD is believed to be 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 has been shown to have restorative functions in rat models of amyotrophic lateral sclerosis (ALS) (Jackson et al., 2014). However, neither NMD nor the mechanisms by which UPF1 achieves this are fully understood (Brogna et al., 2016). Recent evidence from our lab demonstrates novel roles for UPF1 in the nuclei of Drosophila, where it associates with active genes allowing for appropriate mRNA packaging and export (Singh et al., 2019). It is therefore theorized that UPF1 affects mRNA processing before mRNAs reach the cytoplasm, fine-tuning mRNAs from biogenesis.

This project aims to unravel the roles of UPF1 on gene expression through both advanced wet molecular biology experiments and bioinformatic methods. Chromatin immunoprecipitation sequencing (ChIP-seq), RNA-seq, CLIP and similar experiments will be carried out to evaluate the criteria required for UPF1 to bind a nascent transcript. Altogether, the results from this research will give insights into specific effects of this essential protein on gene expression, which will aid the understanding of how UPF1 affects fundamental biological concepts as well as disease.

Overall, taking part in this study will provide invaluable contributions to the front-line research conducted in the Brogna lab. Understanding how UPF1 affects mRNA processing will lead to the explanation of UPF1 behaviour in disease-like environments like ALS, thus allowing for its therapeutic exploitation.

References:

  1. Singh et al. The RNA helicase UPF1 associates with mRNAs co-transcriptionally and is required for the release of mRNAs from gene loci. Elife. 2019 Mar 25;8.
  2. Brogna, S., McLeod, T. and Petric, M. (2016). The Meaning of NMD: Translate or Perish. Trends in Genetics, 32(7), pp.395-407.

BBSRC Strategic Research Priority: Understanding the Rules of Life: Neuroscience and behaviour

    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