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Title: Investigating the mechanisms by which PARP inhibitors increase sensitivity to DNA damaging agents
Author: Löser, Dana A.
ISNI:       0000 0004 2680 5325
Awarding Body: University of Sussex
Current Institution: University of Sussex
Date of Award: 2009
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Damage induced by ionising radiation (IR) is mainly repaired by classical non homologous end joining (D-NHEJ), but a small subset of DSBs is repaired with slow kinetics in an ATM (Ataxia telangiectasia mutated) and Artemis dependent manner. In addition, a PARP-1 dependent NHEJ backup pathway (B-NHEJ) was described, which is thought to function in the absence of D-NHEJ. Using ATM, Artemis or DNA ligase IV deficient mouse embryonic fibroblasts (MEFs) as a model system, the effect of the potent and specific PARP-1/-2 inhibitor KU-0059436 upon clonogenic survival after various types of damage that induce different spectra of SSBs and DSBs was measured. In Artemis or ATM deficient MEFs no sensitising effect of KU-0059436 was detected after neocarzinostatin (NCS) treatment; however PARP inhibition increased sensitivity to IR and methylmethane sulphonate (MMS) markedly. In these cell lines no specific single strand break repair (SSBR) defect was observed, and radio-sensitisation by KU-0059436 was replication dependent. Furthermore PARP inhibition led to increased formation of DSBs, an effect which was augmented in Artemis deficient cells. PARP inhibition in DNA ligase IV deficient cells led to increased sensitivity after damage induction to all agents. However, radiosensitisation by KU-0059436 was replication independent. Results show that PARP inhibition increases the dependence on Artemis and ATM after SSB induction, which is consistent with a model whereby DSBs that arise from SSBs during DNA replication in the presence of a PARP inhibitor require ATM and Artemis for their repair. In cells deficient for DNA ligase IV, PARP inhibition causes additional replication independent sensitisation both by abrogating B-NHEJ and promoting accumulation of replication independent DSBs.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available