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Title: Genome wide analysis of small heat shock proteins involved in yeast ageing
Author: Bloxam, Leanne
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2013
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Ageing is a phenomenon common to almost all living organisms and is characterised by the accumulation of changes with time that are associated with the ever-increasing susceptibility to disease and inevitably death. The rate of ageing is species-specific, indicating a strong genetic component. It is now widely accepted that genes involved in basic cellular processes such as stress resistance, metabolic regulation and genomic stability determine longevity in divergent organisms from yeast to mammals. This suggests that there may be conserved universal mechanisms involved in ageing. Furthermore, lifespan can be increased in all these model organisms by reducing the nutrients consumed - a phenomenon known as dietary restriction (DR). Saccharomyces cerevisiae is a useful model organism in which to study ageing and has been at the forefront of recent pioneering work on the molecular mechanisms underlying lifespan extension by DR. DR can be studied by reducing the glucose concentration from the standard 2% down to 0.5% or below, or by using genetic mimics. However, the exact mechanisms of lifespan extension by dietary restriction remain unclear and highly controversial. Research in our laboratory has identified two proteins in yeast that are induced in response to DR and thus correlate with longevity. Both proteins, Hsp12 and Hsp26, belong to the small heat shock protein (sHsp) family. Previous work by the Morgan laboratory has found that Hsp12 is essential for the longevity effect of DR and have solved the structure of the protein by NMR. Further studies have revealed a genetic interaction between HSP12 and HSP26, as hsp12/hsp26Δ double knockouts show a strongly reduced mean and maximum replicative lifespan. Despite this, the hsp12/hsp26∆ double knockout is not defective in various processes associated with yeast ageing, including stress resistance, rDNA silencing or protein aggregation. To shed light on the mechanisms by which Hsp12 and Hsp26 affect longevity, we employed unbiased approaches of synthetic genetic array (SGA) and quantitative fitness analysis (QFA) to identify genetic interactions of HSP12 and HSP26 on a genome-wide scale. This involved the generation of thousands of double mutant strains and analysis of their growth under various conditions, including DR. Results from the SGA analysis have revealed genetic interactions between HSP12 and HSP26 with the regulation of transcription from RNA polymerase II and processes associated with the mitochondria and vacuoles. QFA data is still to be analysed but ultimately we hope that QFA will re-confirm the genetic interactions identified by SGA analysis. We hope both SGA analysis and QFA data will provide insight into the cellular functions of Hsp12 and Hsp26 and how these proteins affect ageing, in particular lifespan extension by DR.
Supervisor: Morgan, A. L.; Burgoyne, Robert D. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QP Physiology