The genetic landscape of DNA replication in P. falciparum

Theme leader: Dr. Ana-Rita GOMES

DNA replication is a process essential to life. However, mechanisms of genome duplication present a high level of diversity across the tree of life. Although the mechanisms governing this ubiquitous process have been extensively studied in model systems such as yeast or mammalian cells, these systems cover only a fraction of the existing biodiversity and are thus not suitable models for more divergent eukaryotes. The Apicomplexa phylum comprises divergent single-celled eukaryotic organisms with significant clinical relevance, such as Plasmodium parasites, the causative agent of malaria. The development of better and targeted strategies that will efficiently block the development of the parasite has become urgent with the recent emergence of drug resistance to the last efficacious antimalarials.

The pathogenicity of Plasmodium is, in part, linked to its high multiplication rate during vegetative growth within the human host. During this cycle the parasite’s genomic content undergoes several DNA replication rounds, within an enclosed nucleus, after which newly formed, non-condensed, nuclei are segregated into daughter cells, in a process termed schizogony. Currently, we lack basic knowledge such as a clear definition of the parasite’s replicative cycle, how it is regulated and to what extent general eukaryotic DNA replication principles apply to this organism.

Our goal is to perform the first comprehensive study of DNA replication factors and initiation mechanisms in Plasmodium falciparum, the deadliest human parasite. We will achieve this through the following aims:

(1) Identify and characterise factors orchestrating initiation of DNA replication;

(2) Study the genetic landscape of origins of replication;

(3) Explore the genomic determinants of origin specification.