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Title: Cellular and biochemical analyses of TDP1 mediated chromosomal break repair
Author: Wells, Owen Spencer
ISNI:       0000 0004 5355 7822
Awarding Body: University of Sussex
Current Institution: University of Sussex
Date of Award: 2014
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Tyrosyl DNA phosphodiesterase 1 (TDP1) is an end- rocessing enzyme involved in the repair of abortive topoisomerase I (Top1) complexes. Although not essential for survival, a hypomorphic mutation in TDP1 is linked to the autosomal recessive ataxia, spinocerebellar ataxia with axonal neuropathy 1 (SCAN1). SCAN1 is a rare human condition linked with neurodegeneration and ataxic gait and patients are usually wheel chair bound by their early teens. TDP1 primarily cleaves lesions at the 3'-end of DNA breaks and its most prominent substrate is stalled Top1 linked to the 3'-terminus of DNA. The enzymatic mechanism by which TDP1 functions are well understood and inhibitors are now being investigated for treatment of cancer. In contrast, the processes involved in TDP1 recruitment, localisation and regulation during the DNA damage response remain unclear. This thesis investigates how the evolutionarily driven N-terminus of TDP1, not conserved in lower Eukaryotes, is required for optimal cellular protection against genotoxic stress. I also characterise how post-translational modifications of TDP1 allow for efficient repair of transcriptionally associated, chromosomal single-strand breaks and uncover new protein interacting partners of TDP1 and their role in TDP1 mediated repair.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QH0460 Mutations