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Use of single molecule fluorescence and cryo-EM to study the regulation of RNA splicing


Molecular and Cell Biology

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Prof I C Eperon , Dr A Hudson No more applications being accepted Competition Funded PhD Project (European/UK Students Only)

About the Project

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. The PhD project will fit into the heart of this consortium. It will involve the analysis of splicing regulatory proteins, fitted with fluorescent tags, and their association with pre-mRNA and with other proteins in individual complexes. In addition, it will involve developing novel methods for analysing complexes using cryo-electron microscopy. These approaches hold the possibility of making major advances in our understanding.

The University if Leicester is very well equipped for this research. We have several home-built single molecules microscopes, which we have been using for studying splicing for some years, and we have a relatively new and already highly productive cryo-electron microscope.

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/ielts-65

How to apply:
To apply for the PhD please refer to the guidelines and use the application link at https://le.ac.uk/study/research-degrees/funded-opportunities/bbsrc-mibtp
Please also submit your MIBTP notification form at https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/application/


Project / Funding Enquiries: [Email Address Removed]
Application enquiries to [Email Address Removed]


Funding Notes

4 year fully funded BBSRC MIBTP studentship
UK/EU fees and stipend at UKRI rates. For 2020 this will be £15,285 pa

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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