RNA stability and the unfolded protein response

The role of RNA stability and its regulation has become a major area of scientific interest with relevance to a wide range of biological processes. One specific instance is the response to various stresses called the unfolded protein response (UPR) which generally occurs if miss-folded proteins accumulate in the endoplasmic reticulum (ER). The UPR is a well conserved biological response, which results in down regulation of genes encoding secreted proteins and up-regulation of a range of other proteins such as chaperonins. This has specific relevance to a broad range of important biological processes, ranging from diabetes and the response to viral infections to the expression of heterologous proteins in biotechnology. One aspect of the cellular response is the use of a cytoplasmic RNA endonuclease to cleave RNA. This is involved in the activation of a transcription factor (HAC1/XBP1), via an unusual splicing event which occurs in the cytoplasm, intron removal allowing translation and production of the transcription factor which then coordinates the cellular response. In metazoans the endonuclease is also involved in cleaving other transcripts leading to their degradation, reducing the expression of secreted proteins and thus reducing ER stress. The general importance and role of RNA endonucleases is also of major interest.

This project will utilise Aspergillus nidulans, which is well developed as a model organism for the analysis of gene expression and RNA stability studies. It also has significance to the biotechnology industry, where various Aspergillus species are used for the production of proteins. A key issue being to improve protein production by identifying bottlenecks and subsequent strain development. The project will utilise a range of molecular and genetic techniques, including directed gene replacement and protein engineering, mRNA analysis including the characterisation of cleavage events, imaging to monitor RNA and protein localisation and RNAseq and transcriptome analysis. The work may also extend to the analysis of UPR in viral systems using mouse cell culture.

Training:
The candidate will receive a broad training in molecular genetics, developing expertise in working with model microbial systems. This will include training in the analysis of mRNA modification and degradation, directed gene disruption, tagging and mutagenesis, protein characterisation and phenotypic analysis. There is a possibility for interaction with industrial collaborators. A broad generic training program is also in place for postgraduate students ranging from Bioinformatics through to intellectual property and business.