Carroll,_Jean.pdf (5.48 MB)
Investigating aprataxin function: roles in DNA single strand break repair and functional cellular effects
thesis
posted on 2023-06-08, 15:40 authored by Jean CarrollAprataxin protects nuclear and mitochondrial DNA against genotoxic stress, and loss-of-function mutations in the APTX gene cause the autosomal recessive cerebellar ataxia, Ataxia Oculomotor Apraxia 1 (AOA1) in humans. In an effort to extend current understanding of aprataxin function, this thesis examines the roles of aprataxin, especially in response to oxidative damage. Firstly, involvement of aprataxin during the gap-filling as well as the end-processing steps of single strand break repair were demonstrated using an in vitro single strand break repair assay using synthetic DNA substrates, cell-free lysates and/or recombinant proteins. Next, loss-of-function studies were conducted in Aptx-/- mouse embryonic fibroblasts (MEFs) and tissues from adult mice harbouring a toxic gain-of-function mutant form of superoxide dismutase1 (SOD1G93A). Expression of the mutant SOD1G93A enhanced sensitivity to oxidative damage in aprataxin-deleted cells and revealed an accelerated senescence and attenuated somatic growth phenotype. Together these findings suggest that aprataxin function is involved in optimal repair of single strand breaks and is therefore critical in maintaining cell function in situations of elevated oxidative stress.
History
File Version
- Published version
Pages
208.0Department affiliated with
- Biochemistry Theses
Qualification level
- doctoral
Qualification name
- phd
Language
- eng
Institution
University of SussexFull text available
- Yes
Legacy Posted Date
2013-09-24Usage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC