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The role of PARP-1 and XRCC1 in homologous recombination.

Parker, Kayan M (2008) The role of PARP-1 and XRCC1 in homologous recombination. PhD thesis, University of Sheffield.

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Abstract

In this thesis, the role of PARP-1 and XRCC1 in camptothecin (CPT) induced homologous recombination (HR) has been elucidated. The aims of this study were to investigate the role of PARP-1 and XRCC1 in the repair of CPT-induced damage, to find out if PARP-1 was involved in single strand break (SSB) repair, and to investigate the role of PARP inhibitors in the repair of CPT-induced damage. Cells lacking PARP-1, and wildtype cells treated with PARP inhibitors, were found to have increased sensitive to CPT. This increased sensitivity was found to correlate to an increased amount of DNA double-strand breaks (DSBs), and an increased number of cells containing RAD51 foci. This is an indication of an increased amount of HR in these cells. Cells deficient in XRCC 1 were also found to have an increased sensitivity to CPT, increased levels of DSBs and an increased number of cells containing RAD51 foci. A mutant XRCC1 cell line containing a disrupted BRCT 1 motif showed even further sensitivity to CPT. This motif interacts with PARP-1, and when disrupted, seems to inhibit the protein in some way. We have concluded that in the absence of PARP-1 or XRCCI, the repair of SSBs is slower. These breaks are therefore more likely to encounter the replication machinery, where they become DSBs. These breaks are repaired by HR. Cells that lack both PARP1 and XRCC1 may have even slower SSB repair, as they have an increased amount of cells containing RAD51 foci, which indicates increased HR. PARP inhibitors used in conjunction with CPT increases the cytotoxicity of CPT, which could help in chemotherapy. In the future, maybe inhibiting XRCC1 as well could further enhance this affect.

Item Type: Thesis (PhD)
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield)
Other academic unit: Division of Genomic Medicine
Identification Number/EthosID: uk.bl.ethos.444271
Depositing User: EThOS Import Sheffield
Date Deposited: 11 Sep 2019 14:05
Last Modified: 11 Sep 2019 14:05
URI: http://etheses.whiterose.ac.uk/id/eprint/21807

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