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Mechanisms Of Genome Stability And Dna Repair In Plasmodium Falciparum

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Abstract

The human malaria parasite Plasmodium falciparum replicates within circulating red blood cells where it is subjected to conditions that frequently cause DNA damage. The repair of DNA double stranded breaks (DSBs) is thought to rely almost exclusively on homologous recombination (HR) due to a lack of efficient non-homologous end joining (NHEJ), however given that the parasite is haploid during this stage of its lifecycle, the mechanisms involved in maintaining genome stability are poorly understood. This work investigates methods of DNA repair and how these pathways function in maintaining the P. falciparum genome. First, we investigate the essentiality of Rad51 in response to DNA damage and describe how the parasite developmental stage dictates DNA repair ability based on the possibility of HR repair. Life cycle stage is shown to mediate resistance to DNA damage caused by X-ray irradiation likely due to the parasite’s ability to perform HR at different stages of the erythrocytic cycle. By creating a Rad51 dominant negative mutant we find that Rad51 may not be an essential protein for HR repair and the loss of function differentially affects stage-specific repair. Secondly, we show that parasites utilize a competitive balance between de novo telomere addition, also called “telomere healing”, and HR to stabilize chromosome ends. Products of both repair pathways were observed in response to DSBs that occurred spontaneously during routine in vitro culture or resulting from experimentally induced DSBs, demonstrating that both pathways are active in repairing DSBs within subtelomeric regions and the pathway choice is sequence dependent. Finally, we discuss how this research fits into the field of knowledge about DNA repair in P. falciparum and how evolution of the DNA repair pathways has mediated plasticity of the genome.

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2017

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DNA repair; homologous recombination; Malaria; Plasmodium falciparum; Rad51; telomere healing

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Immunology & Microbial Pathogenesis

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Doctor of Philosophy

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Government Document

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Attribution-NonCommercial-NoDerivatives 4.0 International

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dissertation or thesis

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