Hyde, Anne Cathrine ORCID: 0000-0001-6660-8893
(2025)
Investigation of ageing associated inflammation and genomic instability in zebrafish.
PhD thesis, University of Sheffield.
Abstract
The global population is living longer thanks to advancements in treatments for diseases that previously significantly shortened lifespans. However, these extra years are often accompanied by ill health and frailty, placing a considerable burden on both individuals and society, prompting the requirement into further research. One of the primary hallmarks of ageing is genomic instability, suggesting that increased DNA damage is partly responsible for why we age. One of the most common forms of DNA damage is the incorporation of single ribonucleotides into the DNA. A ribonucleotide is more reactive than a deoxyribonucleotide and if not removed, it can cause replication and transcription stalling as well as DNA breaks.
Here I use zebrafish (Danio rerio) as a model to study whether a reduced ribonucleotide removal activity from the genome is related to why someone becomes frail. I have made a frailty index for zebrafish, and I see that the frail fish have a reduced ability to cleave single ribonucleotides in the brain. This suggests that removal of ribonucleotides is important in robust ageing, and a loss of this function might be linked to frailty.
Further, I investigate FASTKD2 as a potential alternative enzyme that can remove single ribonucleotides from the mitochondrial DNA by creating a fastkd2 homozygous knockout zebrafish mutant. I show that whilst the mutant is viable, it is not efficient in producing energy, and it has no defects in single ribonucleotide removal. I also create a mutant for APRATAXIN, which resolves alternative ligation products, but is hindered by ribonucleotides. I show that the aprataxin mutant has reduced movement abilities. Lastly, I attempt to rescue a lethal zebrafish phenotype caused by loss of NuMA in zebrafish larvae by injecting parts of human cDNA NuMA into the genome of the mutant. However, I was unsuccessful in causing a rescue.
Metadata
Supervisors: | van Eeden, Fredericus and El-Khamisy, Sherif and Villa-Uriol, Maria-Cruz |
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Keywords: | Ageing, Zebrafish, DNA damage, RNaseH2 |
Awarding institution: | University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) |
Depositing User: | Dr Anne Cathrine Hyde |
Date Deposited: | 04 Jul 2025 10:27 |
Last Modified: | 04 Jul 2025 10:27 |
Open Archives Initiative ID (OAI ID): | oai:etheses.whiterose.ac.uk:36966 |
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