Project Summary/Abstract: Malaria continues to be a major cause of morbidity and mortality among people living in the tropical and subtropical regions of the world. The ability of parasites to continuously generate sequence diversity within their genomes is a major contributor to the inability to develop effective erythrocytic stage vaccines and to the ever-present problem of drug resistance. Yet, key gaps remain in our understanding of how the parasite genome is maintained. Our long-term goal is to identify pathways that are crucial to maintaining the parasite genome and understand how these repair pathways impact mutability and genome plasticity. Translesion (TLS) polymerases are specialized DNA polymerases that are capable of continuing DNA synthesis through damage bases and difficult templates, though they accomplish this in an error prone manner. In model systems, TLS polymerases generate the majority of novel mutations. There are only two TLS polymerase present in the primate malaria genomes, Rev 1 and pol ?. Our hypothesis is that these polymerases play a crucial role in parasite genome maintenance and contribute to persistence of and pathogenesis of malaria by a) driving the generation of antigenic diversity by promoting homologous recombination (HR) between semi-homologous but non-identical members of multicopy gene families and b) contributing to the generation of sequence variation throughout the genome and in turn to the development of drug resistance. Using genome editing techniques, mutagenesis and SMRT sequencing techniques, we seek to uncover the role of TLS polymerases in the human malaria parasite, Plasmodium falciparum. Our proposed research will uncover unique aspects of Plasmodium DNA repair that will be important for understanding malaria and to those that study genome maintenance in general. Our aims are designed to have direct impact on the important clinical aspects of malaria, the parasite's propensity to develop drug resistance and evade the host immune system. This study addresses an important and neglected aspect of parasite biology.
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NIH ExPorter