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

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

This project’s specific objective is to study the molecular role(s) that the RNA helicase UPF1 plays in RNA processing. UPF1 is a key player in nonsense-mediated mRNA decay (NMD), it is universally conserved in eukaryotes and is essential to the development of many organisms [1]. UPF1 is a candidate treatment for amyotrophic lateral sclerosis (ALS), a progressive and eventually lethal human neurodegenerative disease for which there is no satisfactory treatment: expression of human UPF1 in rat ALS models overcomes the pathology caused by over-expression or mutation of the RNA-binding protein TDP-43 [2, 3]. However, neither the functional significance of NMD nor the role that UPF plays in NMD or in ameliorating ALS is sufficiently understood [4]. Although it is widely believed that UPF1 is conserved solely because it is needed in order to target particular mRNAs for NMD[5], there is emerging evidence that UPF1 may play broader role(s) in gene expression than so far envisaged, including participation in nuclear RNA processing [6].

This project’s specific objective is to study the molecular role(s) that the RNA helicase UPF1 plays in RNA processing. Specifically, building on our recent report that UPF1 associates with nascent pre-mRNA transcripts and that it plays genome-wide roles in nuclear RNA-based processes – including transcription, mRNA export and most strikingly mRNA transcription site retention - this project aims to unveil what specific molecular function(s) UPF1 fulfils on nascent ribonucleoprotein (RNP) complexes and which of these processes are required for mRNA release from transcription sites, for correct pre-mRNA processing, to prevent mRNP aggregation and to facilitate mRNA export to the cytoplasm. Although this project aims to improve our understanding of basic aspects of gene expression and hence will primarily further the knowledge of fundamental biology – a quintessential requirement to any of the more applied biomedical research enterprises aimed at improving specific human conditions - in this specific instance, the results should provide direct useful insights into the mechanisms causing ALS and might provide knowledge which could help in the development of a treatment for this devastating neurodegenerative disease caused by defects in RNA processing.

The student will conduct this research in either yeast or Drosophila, two amenable experimental organisms, and we will provide advanced training in molecular biology, yeast (or Drosophila) molecular genetics, genomics (analysis of next-generation sequencing) and proteomics (high-throughput mass spectrometry). The study will require extensive bioinformatics analysis. Our collaborators at either UoB Centre of Computational Biology or at other UK institutions will provide Training/support in the required software and scripting.


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Please find additional funding text below. For further funding details, please see the ‘Funding’ section.

The School of Biosciences offers a number of UK Research Council (e.g. BBSRC, NERC) PhD studentships each year. Fully funded research council studentships are normally only available to UK nationals (or EU nationals resident in the UK) but part-funded studentships may be available to EU applicants resident outside of the UK. The deadline for applications for research council studentships is in January each year.

Each year we also have a number of fully funded Darwin Trust Scholarships. These are provided by the Darwin Trust of Edinburgh and are for non-UK students wishing to undertake a PhD in the general area of Molecular Microbiology. The deadline for this scheme is also in January each year.

Please note the only funding available for our PhD is via the Scholarships mentioned. All applicants should indicate in their applications how they intend to fund their studies. Any academically suitable applicant that does not indicate how they intend to fund their studies will be considered for the Darwin and/or the Elite Scholarships if not already indicated. We can only consider applicants who have their own funding or wish to apply for their own funding or are successful in gaining a Scholarship.

Funding Notes

Research Council Studentships are available for UK applicants. EU applicants resident in the UK may also be eligible. Non-UK students interested in molecular microbiology may apply for a Darwin Trust Scholarship.

We have a thriving community of International PhD students and encourage applications at any time from students of any nationality either able to fund their own studies or who wish to apply for their own funding (e.g. Commonwealth Scholarship Council, Islamic Development Bank).

For further information on funding see View Website

References

1. Brogna, S. and J. Wen, Nonsense-mediated mRNA decay (NMD) mechanisms. Nat Struct Mol Biol, 2009. 16(2): p. 107-13.
2. Jackson, K.L., et al., Preservation of forelimb function by UPF1 gene therapy in a rat model of TDP-43-induced motor paralysis. Gene Ther, 2015. 22(1): p. 20-8.
3. Barmada, S.J., et al., Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1. Proc Natl Acad Sci U S A, 2015. 112(25): p. 7821-6.
4. Brogna, S., T. McLeod, and M. Petric, The Meaning of NMD: Translate or Perish. Trends Genet, 2016. 32(7): p. 395-407.
5. Karousis, E.D., S. Nasif, and O. Muhlemann, Nonsense-mediated mRNA decay: novel mechanistic insights and biological impact. Wiley Interdiscip Rev RNA, 2016. 7(5): p. 661-82.
6. Varsally, W. and S. Brogna, UPF1 involvement in nuclear functions. Biochem Soc Trans, 2012. 40(4): p. 778-83.

How good is research at University of Birmingham in Biological Sciences?

FTE Category A staff submitted: 42.80

Research output data provided by the Research Excellence Framework (REF)

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