Authors

S Stanojcic²; N Kuk²; I Ullah¹; Y Sterkers²; C J Merrick¹;  ¹ Keele University;  ² University of Montpellier and Centre Hospitalier Universitaire, France

Discussion

The mechanics of DNA replication and the cell cycle have been well characterized in model organisms, but less is known about these basic aspects of cell biology in Apicomplexan parasites, which do not divide by canonical binary fission but undergo unconventional cycles. Schizogony in Plasmodium generates ~16-24 new nuclei via independent, asynchronous rounds of genome replication prior to cytokinesis, and little is known about the control of DNA replication that facilitates this. We have characterised DNA replication dynamics in P. falciparum throughout schizogony, using DNA fibre labelling and combing to visualise replication forks at a single-molecule level. We show that replication origins are very closely spaced in Plasmodium compared to most model systems, and that replication dynamics vary across schizogony, with faster synthesis rates and more widely-spaced origins in early trophozoites, versus slower synthesis and closer-spaced origins later on. This is the opposite of the pattern usually seen across S-phase in human cells, when a single genome is replicated. Replication forks also stall at an unusually high rate throughout schizogony. Our work explores DNA replication in Plasmodium in unprecedented detail and opens up tremendous scope for analysing cell cycle dynamics and developing interventions that target this unique aspect of malaria biology.