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The University of Southampton
Interdisciplinary Research Excellence

Post-transcriptional control of gene expression following cell stress Event

Time:
17:00 - 18:00
Date:
3 December 2012
Venue:
Building 85, Room 2207

For more information regarding this event, please telephone Beatrice Murphy on 023 8059 5374 or email B.J.Murphy@soton.ac.uk .

Event details

Under conditions of patho-physiological cell stress post transcriptional regulation of gene expression is achieved by the reprogramming protein synthesis. For example, we have shown post-transcriptional control makes a major contribution to overall gene expression changes that occur during the regulation of apoptosis by TRAIL and following exposure of cells to DNA damaging agents. This regulation is brought about by interaction of RNA-binding proteins with specific regulatory elements in their cognate mRNAs that control mRNA stability and translation.

In this regard, we have shown that translational up-regulation of many critical components of the nucleotide excision repair pathway following DNA damage requires RNA regulatory elements within the 5' and 3' UTRs of mRNAs that remain polysomally associated. We have shown that regulatory upstream open reading frames are enriched in this group of mRNAs. Importantly, we show that a common polymorphism in an uORF in the 5' UTR of the critical DNA repair enzyme ERCC5 determines sensitivity to platinum-based chemotherapy by controlling ERCC5 translation.


In apoptotic cells we have examined the RNA-binding proteins that allow specific protein sub-complexes to control cytoplasmic gene expression. We show that polypyrimidine tract binding (PTB) protein is central to one such complex that forms in apoptotic cells. Thus, during TRAIL mediated apoptosis there is a change in the repertoire of RNA binding proteins with which PTB interacts. We show that altering the cellular levels of PTB and its binding partners, either singly or in combination, is sufficient to directly change the rates of apoptosis with increased expression of PTB, YBX1, PSF and NONO/p54nrb accelerating this process.
Taken together, our data shows that it is possible to dictate cell fate by modulating cytoplasmic gene expression pathways alone.

Speaker information

Professor Anne Willis,Director of MRC Toxicology Unit, University of Lhwsester

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