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Title: Mathematical modelling of the effect of ribosome recycling on messenger RNA translation and degradation in Saccharomyces cerevisiae
Author: Marshall, Elizabeth
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2014
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I present the results of my analysis of the final stage of gene expression, the translation of messenger RNA. Translation is carried out by large molecular motors called ribosomes, which move along the mRNA molecule in a stepwise fashion, producing a polypeptide chain. Translation can be modelled as a driven diffusion process, and I extend the Totally Asymmetric Simple Exclusion Process (TASEP) to consider the possibility that ribosomes that terminate from the lattice can rejoin the lattice to reinitiate translation, known as ribosome recycling. Inclusion of recycling leads to marked changes in the phase transition boundaries when compared with a non-recycling lattice, with extension and expansion of the so-called maximal current regime, where protein production is at optimal levels. Recycling makes this phase accessible even at low values of de novo initiation. Furthermore, recycling leads to a sharp peak in particle current on the low density-high density phase boundary, with a decrease in current within the high density regime. Simulations of real biological sequences from the budding yeast Saccharomyces cerevisiae suggest that increasing ribosomal availability can, in fact, reduce the efficiency of protein production in a sequence-dependent manner, particularly for mRNAs encoding proteins with a stressresponse function. Consistent with this, separating the yeast transcriptome into phase transition classes brings to light class-dependent features including parameter values and protein functionality. The role ribosome recycling plays in determining the lifetime of a messenger RNA is also studied. Ribosome initiation has a stabilising effect; counteracting this is ribosome termination, which enhances removal of proteins that protect the mRNA 'tail', exposing it to degradation enzymes. Mathematical modelling of this process shows that recycling can affect mRNA lifetimes in a phase-dependent manner that is not straightforward. This indicates that there are additional, important factors involved in the regulation of decay beyond the interplay between termination and initiation. The research reported in this thesis shows that systems biology can offer insight into a complex stage of gene regulation, and has a significant role to play in future research.
Supervisor: Not available Sponsor: Biotechnology and Biological Sciences Research Council (BBSRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Gene expression ; RNA ; Ribosomes ; Saccharomyces cerevisiae