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Investigating aprataxin function: roles in DNA single strand break repair and functional cellular effects

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posted on 2023-06-08, 15:40 authored by Jean Carroll
Aprataxin 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.

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  • Published version

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208.0

Department affiliated with

  • Biochemistry Theses

Qualification level

  • doctoral

Qualification name

  • phd

Language

  • eng

Institution

University of Sussex

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  • Yes

Legacy Posted Date

2013-09-24

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