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Detection in cells of protein interactions on pre-mRNA during the regulation of splicing


Project Description

One of the biggest challenges in molecular biology is presented by the selection of sites for RNA splicing. We cannot overstate its importance or apparent complexity. Splicing determines which mRNA and protein sequences a gene expresses. It is accurate, removing introns of 102-106 bases, but paradoxically flexible in mammals, where most genes produce multiple isoforms of mRNA. These may produce proteins with different functions (up to 1,800 functional isoforms of neurexin 3, for example) and switching is involved in memory, development, differentiation, signalling and disease. Numerous regulatory proteins and their binding sites have been identified by ensemble and ‘omic’ approaches, but our understanding of their mechanisms and functional integration remains very poor. We have recently made breakthrough findings by combining single molecule methods and chemical biology. These methods and a transformative vision of the dynamics of the process leave us poised to discover the mechanisms of selection.

This research is based on a multi-disciplinary group from the Universities of Leicester, Strathclyde and Glasgow. This group brings together expertise in nano-engineering, bio-organic chemistry, photonics, structural biology, RNA splicing and molecular biology, and has been funded by a BBSRC sLOLA grant for 5 years. This PhD project is concerned with in vivo tests of the predictions from our in vitro results, and therefore provides a very important complement to the more biophysical work. It will involve the use of RNAi and over-expression, mutations and CLIP to test protein interactions in cells. More direct evidence will come from biotin proximity ligation assays, in vivo protein-protein interaction assays based on fluorescence microscopy and novel methods for targeting protein cross-linking to proteins on specific pre-mRNA substrates.

The University if Leicester is very well equipped for this research, with extensive conventional cell microscopy resources and expertise in cell and molecular biology in the supervisors’ labs.

Eligibility:

UK/EU applicants only.

Entry requirements:

Applicants are required to hold/or expect to obtain a UK Bachelor Degree 2:1 or better in a relevant subject.

The University of Leicester English language requirements apply where applicable: https://le.ac.uk/study/research-degrees/entry-reqs/eng-lang-reqs

How to apply:

Please refer carefully to the application guidance and apply using the online application link at https://le.ac.uk/study/research-degrees/funded-opportunities/bbsrc-mibtp

Project / Funding Enquiries:
Application enquiries to
Closing date for applications: Sunday 12th January 2020

Funding Notes

4 year MIBTP studentship offering

Stipend at UKRI rates

Tuition fees at UK/EU rates

References

Jobbins, A.M., Reichenbach, L.F., Lucas, C.M., Hudson, A.J., Burley, G.A., & Eperon, I.C.* (2018). The mechanisms of a mammalian splicing enhancer. Nucleic Acids Research 46, 2145-2158 (doi: 10.1093/nar/gky056). Breakthrough article.

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