Principal Supervisor: Dr. Saverio Brogna, School of Biosciences
Co-supervisor: Dr. Pawel Grzechnik, School of Biosciences
PhD project title: Eukaryotic RNA biology: understanding the mechanism linking pre-mRNA processing to translation and NMD
University of Registration: University of Birmingham
Nonsense-mediated mRNA decay (NMD) describes the observation that premature termination of translation can cause more rapid degradation of mRNAs. NMD is a major determinant of gene expression, shapes transcriptomes and is a promising drug target – but its mechanism(s) is not understood in any organism (1,2). The research in the Brogna lab is directed at understanding this process, and especially to explain an unexpected link between NMD and pre-mRNA splicing in the nucleus. Whilst it is widely believed that the exon junction complex (EJC) mediates this link in mammalian cells, we have gathered compelling evidence that an EJC-like complex is not involved in splicing-dependent NMD – neither in budding nor fission yeast, and maybe not even in Drosophila (3,4). These findings re-open two fundamental questions: what other mechanisms couple pre-mRNA processing with translation in eukaryotes; and what other, still unrecognized, basic functions do EJC proteins carry out? We are interested in understanding what these mechanisms might be and what additional roles NMD and EJC factors play in pre-mRNA processing and translation. While the PhD project will follow this general research plan, it will focus on a specific question that will be defined at the start, to match interest and aptitude of the student with the state of the field at the time. As well as modern molecular biology procedures, the project might involve one or more of the following leading-edge techniques: CRISPR-Cas9 gene editing, NET-seq, ChIP-seq and associated bioinformatics.
- Brogna, S. and Wen, J. (2009) Nonsense-mediated mRNA decay (NMD) mechanisms. Nat Struct Mol Biol, 16, 107-113.
- Brogna, S., McLeod, T. and Petric, M. (2016) The Meaning of NMD: Translate or Perish. Trends Genet, 32, 395-407.
- Choudhury, S.R., Singh, A.K., McLeod, T., Blanchette, M., Jang, B.Y., Badenhorst, P., Kanhere, A. and Brogna, S. (2016) Exon junction complex proteins bind nascent transcripts independently of pre-mRNA splicing in Drosophila melanogaster. Elife, 5.
- Wen, J. and Brogna, S. (2010) Splicing-dependent NMD does not require the EJC in Schizosaccharomyces pombe. The Embo Journal, 29, 1537-1551.
BBSRC Strategic Research Priority: Molecules, Cells and Systems, Food Security, Bioenergy and Industrial Biotechnology
Techniques that will be undertaken during the project:
The project will provide advanced training in:
- Molecular biology
- Yeast (or Drosophila) molecular genetics,
- Genomics (analysis of next generation sequencing)
- Proteomics (high-throughput mass spectrometry).
Contact: Dr. Saverio Brogna, School of Biosciences