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Title: Genetic interactions of the Saccharomyces cerevisiae DNA Repair Factor PSO2
Author: Ward, Thomas Anthony
Awarding Body: Oxford Brookes University
Current Institution: Oxford Brookes University
Date of Award: 2013
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DNA interstrand cross-links (ICLs) present a major challenge to cells, covalently binding the two DNA strands together and preventing fundamental cellular processes, such as transcription and replication. Failure to repair such les ions can lead to the formation of DNA double-strand breaks (DSBs), gross-chromosomal rearrangements (GCRs) and ultimately, cell death. ICL-inducing agents have been used clinically for the management of cancers, and increased tolerance of these lesions has been implicated in the development of resistance to such treatments which might, in part, be mediated by DNA repair. This repair requires the orchestration of many different DNA repair mechanisms, such as nucleotide excision repair (NER), trans-lesion synthesis (TLS) and homologous recombination (HR), and the action of factors required specifically for ICL repair, such as the 5'-3' exonuclease Pso2/SNM IA and members of the vertebrate Fanconi anemia (FA) pathway. Disruption of Saccharomyces cerevisiae PS02 confers sensitivity to ICL-inducing agents but no other forms of DNA damage. Here I show that in the absence of Ps02, a complex of the MutSĪ± (Msh2-Msh6) mismatch repair (MMR) factor, the mitochondrial replication and repair protein Mgm101 and the FANCM homologue Mph1 facilitates the loading of Exol to chromatin to allow for the repair of ICLs. Moreover, S. cerevisiae homologues of the FA proteins FANCJ (Chll) and FANCP (Slx4) are also required for this FA-like pathway, which leads to TLS, HR and non-homologous end-joining (NHEJ). The Ps02-dependent and FA-like pathways are controlled by NER and protect cells against DSBs, GCRs and the constitutive activation of the intra S-phase checkpoint following ICL induction. In vertebrate cells, incision of ICLs requires structure-selective endonucleases that cleave stalled replication forks that converge on an ICL. The work presented in this thesis shows that RadI, the S. cerevisiae homologue for one of these endonucleases (XPF), is essential for the repair of ICLs in the absence of NER. Rad I controls an S-phase specific pathway, distinct from the Pso2-dependent and FA-like pathways, but requires TLS and HR. These data suggest that the repair of ICLs in S. cerevisiae and higher eukaryotes is more comparable than previously thought, making budding yeast an attractive model organism for the study of ICL repair.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available