Wells,_Owen_Spencer.pdf (22.48 MB)
Cellular and biochemical analyses of TDP1 mediated chromosomal break repair
thesis
posted on 2023-06-08, 18:05 authored by Owen WellsTyrosyl 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.
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- Published version
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206.0Department affiliated with
- Biochemistry Theses
Qualification level
- doctoral
Qualification name
- phd
Language
- eng
Institution
University of SussexFull text available
- Yes
Legacy Posted Date
2014-09-08Usage metrics
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