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How do cancer associated changes in RNA processing mechanistically affect protein structure and diversity?


Project Description

Mis-regulation of gene expression is a key contributor in driving tumorigenesis. This can happen at the point of alternative splicing. RNA-Seq data from a range of cancer patients has shown there are 1000s of alterations in splicing between normal and cancer samples. These changes in mRNA isoform have been predicted to alter the composition of the encoded protein, specifically in the inclusion or exclusion of protein- protein and protein- RNA interaction domains.What is yet to be understood is the functional consequences of the changes in splicing. This understanding will provide new therapeutic targets to tackle diseases caused by mis-regulation of splicing eg. SMA.

This project aims to understand whether these altered RNA transcripts are decoded by the ribosome into protein and the precise structural implication this will have on the cancer proteome. Downstream effects of modulating protein binding will also be explored. This will be achieved using biochemical and structure analysis (eg. X-ray crystallography, with the potential to take advantage of the University’s recent £17 million investment in the Astbury Biostructure Laboratory). The extent of mRNA translational regulation with be assessed using Next Generation Sequencing methods within LeedsOmics (http://www.leedsomics.org/).

Background
Alternative mRNA splicing provides enables the generation of protein diversity, allowing synthesis of alternative protein isoforms with distinct biochemical activities. Splicing is a key point in gene expression regulation, which when mis-­regulated contributes to human disease eg. cancer. Disease causing alternative splicing events have recently become relevant therapeutic targets eg SMA.
However, the functional consequence of splicing has so far been less well studied, both in terms of;
i) How changes in transcript identity affect mRNA translation
ii) How the resulting changes alter the structure of function of the translated protein

This work will provide exciting insight into how changes in gene expression contribute to altered protein function and will molecularly dissect the mechanistic link between RNA processing in the nucleus with mRNA translation in the cytoplasm.

Objectives
1) Characterize the mechanistic impact of cancer associated mutations on alternative splicing and the transcriptome
2) Assess how altered RNA processing affects mRNA translation.
3) Determine the molecular and structural consequences of cancer driven changes to the proteome.

Novelty
Here we will use RNA-­seq data from cancer patients to mechanistically probe the link between changes in alternative splicing and mRNA translation, to understand how this affects the structural proteome. Therefore we will be using patient data to drive basic biochemical mechanistic study of gene expression.

Timelines
Recent analysis of patient transcriptomes from a range of different cancer types has been performed, highlighting the importance of alternative splicing patterns on proteome diversity. However, what is currently missing is an assessment of the effect of the changes in splicing on mRNA translation and protein structure/function.

Experimental Approaches
We will use an exciting combination of:
-­Next Generation Sequencing to study both transcriptome (RNA-­Seq) and changes in mRNA translation (Ribo-­Seq)
-­Protein-­protein/RNA interaction assays, structural methods (X-­ray crystallography, computational modelling) and functional cell-­based assays.

To find out more about the Aspden Group:
https://aspdenlab.weebly.com/

Funding Notes

BBSRC White Rose Mechanistic Biology DTP 4 year studentship.

Studentships covers UK/EU fees and stipend (c.£14,553) for 4 years to start in Oct 2018. Applicants should have/be expecting at least a 2.1 Hons. degree in a relevant subject. EU candidates require 3 years of UK residency in order to receive full studentship.

Not all projects advertised will be funded; the DTP will appoint a limited number of candidates via a competitive process and the projects selected by the successful candidates will be funded.

There are 2 stages to the application process. Please see our website for more information: View Website

References

Aspden, J. L., Eyre-Walker, Y. C., Philips, R., Amin, U., Mumtaz, A. S., Brocard, M., Couso, J. P. Extensive translation of small ORFs revealed by Poly-Ribo-Seq. eLife 10.7554/eLife.03528 (2014).

Taliaferro, J.M., Aspden, J. L., Bradley, T., Marwha, D., Blanchette, M.,Rio, D. C. Two new and distinct roles for Drosophila Argonaute-2 in the nucleus: alternative pre-mRNA splicing and transcriptional repression.
Genes & Development 27, 378-389 (2013).

Chavali PL, Stojic L, Meredith LW, Joseph N, Nahorski MS, Sanford TJ, Sweeney TR, Krishna BA, Hosmillo M, Firth AE, Bayliss R, Marcelis CL, Lindsay S, Goodfellow I, Woods CG, Gergely F. Neurodevelopmental protein Musashi-1
interacts with the Zika genome and promotes viral replication. Science. 2017
357(6346):83- 88. (2017)

Haq T, Richards MW, Burgess SG, Gallego P, Yeoh S, O'Regan L, Reverter D, Roig J, Fry AM, Bayliss R. Mechanistic basis of Nek7 activation through Nek9 binding and induced dimerization. Nat. Commun. 6, 8771. (2015)

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

FTE Category A staff submitted: 60.90

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

Click here to see the results for all UK universities

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