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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Date of Award

Fall 2013

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Department of Biology

Abstract

Malaria is a deadly infection caused by a single celled protozoan of the Plasmodium genus. Plasmodium spp. are transmitted to humans by mosquitoes, and initially invade the liver, but the disease is caused by the blood stage of the infection. Approximately 500 million cases of malaria are documented annually and over 1 million of those result in death. Plasmodium falciparum is the most lethal of five species known to infect humans. To further compound this problem, drug-resistant parasite strains have been documented for every currently available antimalarial drug, making the need to identify new drug targets more urgent than ever. Modern genetics have found that more than 50% of the Plasmodium genome codes for proteins of unknown functions, with no significant sequence homology to any known eukaryotic genes. Recent advances in forward genetics and the use of transposable elements to manipulate the genome of P. falciparum have made tremendous contributions to discovering the functions of these unknown genes, which is critical to rapidly advance antimalarial drug development. In this study we have identified a gene of unknown function, PF3D7_1143500, that is significant for intraerythrocytic development of Plasmodium. This gene exhibits weak similarities to the human regulator of chromatin condensation 1 protein (RCC1) and appears to belong to the class of RCC1-like proteins that perform diverse functions in eukaryotes. A thorough cellular and molecular analysis of an insertional knockout mutant of PF3D7_1143500 in P. falciparum has revealed a critical role for this gene in the production of merozoites during the intraerythrocytic cycle. The insertional mutant parasite strain displays a significant delay in initiating nuclear division, which results in a 40% reduction in the number of merozoites produced at the end of the intraerythrocytic cycle, thereby severely attenuating the parasite growth rate. PF3D7_1143500 localizes to the microtubule organization centers within the nucleus during the early stages of parasite development, suggesting it functions in regulating mitosis. Since cell cycle regulatory mechanisms are largely unknown in Plasmodium, the identification of this novel RCC1-like protein promises to offer new insights into this critical biological pathway that has high potential as an antimalarial drug target.

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