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Nuclear regulation of mRNA stability in response to cellular stress

Principal Supervisor: Dr Pawel Grzechnik - School of Biosciences

Co-supervisor: Dr Saverio Brogna

PhD project title: Nuclear regulation of mRNA stability in response to cellular stress

University of Registration: University of Birmingham

Project outline:

Nuclear RNA metabolism involves transcription of genetic information encoded in DNA to RNA, followed by RNA processing or degradation. Any defect in this process may lead to pathological outcomes and ultimately to cell death. In eukaryotic cells, the major RNA metabolism regulatory mechanisms are coordinated through specific factors (CTD readers) interacting with the RNA Polymerase II (Pol II) C-terminal domain (CTD). Although CTD readers emerge as central players in nuclear RNA metabolism their functions are still not fully uncovered. Therefore our lab aims to draw a broad picture how CTD readers control nuclear RNA metabolism and consequently, gene expression in eukaryotic cells. A thorough knowledge regarding gene expression regulation is of central importance for understanding the basic principles of genetic diseases.

In reaction to environmental stressors like heat, high salt or reactive oxygen species concentration, stress response mechanisms induce the expression of genes facilitating cell survival. Promoters of stress-induced genes play crucial role in stress response as they force cytoplasmic localization and translation of mRNA in adverse conditions. In contrast to house-keeping genes activated by TFIID, stress-induced gene expression is promoted by the SAGA complex, which modulates chromatin structure, recruits pre-initiation complexes, promotes transcription elongation and mRNA export. The aim of this project is to uncover another potential mechanisms through which promoters control gene expression beyond transcription initiation.

Instantaneous expressional shutdown of stress-induced genes when the stress has passed is the next essential step allowing an entry into the recovery phase. Therefore, extensive transcription of stress-induced genes correlates with the increased degradation rate of their mRNA. Our preliminary analysis has revealed a link between the SAGA complex and CTD reader-dependent nuclear RNA degradation. This data suggests that transcriptional activators determine the choice of the RNA degradation pathway of the transcribed mRNA. Therefore, the successful student will investigate the connection between SAGA-dependent transcription and nuclear RNA degradation of stress-induced genes in yeast S. cerevisiae. Ultimately, this project will uncover a new pathway, which regulates cellular stress response in eukaryotic cells.

BBSRC Strategic Research Priority: Molecules, cells and systems

Techniques that will be undertaken during the project:

The project will employ a wide variety of classic and modern biochemical and cell biology techniques including molecular cloning, Northern and Western Blot, RNA sequencing (RNA-seq), real-time PCR (qPCR), cell sorting, yeast growth and survival assays.

Contact: Dr Pawel Grzechnik, University of Birmingham