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

Carroll, Jean (2013) Investigating aprataxin function: roles in DNA single strand break repair and functional cellular effects. Doctoral thesis (PhD), University of Sussex.

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Abstract

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.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics
Depositing User: Library Cataloguing
Date Deposited: 24 Sep 2013 14:12
Last Modified: 08 Dec 2015 14:06
URI: http://sro.sussex.ac.uk/id/eprint/46135

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