Cell cycle checkpoint activity in the malaria parasite Plasmodium falciparum

Plasmodium spp. have different modes of cell division from most eukaryotes. Little is known about how these are controlled and cell-cycle checkpoints are particularly poorly characterised. However, parasites can arrest their cell cycle when treated with the frontline antimalarial drug artemisinin, and artemisinin-resistant parasites can modulate their cell-cycle progression, so it is very important to understand these aspects of Plasmodium biology. Here, we show that P. falciparum displays hallmarks of an intra-S-phase checkpoint when exposed to DNA damage, including acute reduction of DNA replication and phosphorylation of a putative damage-marker histone. Compounds that inhibit human checkpoint kinases can inhibit this arrest of DNA replication, and synergise with DNA damage in parasite killing. This suggests the existence of checkpoint kinase activity in P. falciparum, yet these kinases have no clear homologues in Plasmodium genomes. We hypothesise that phosphatidylinositol 3-kinase - an essential lipid kinase - may moonlight in this role: it is the closest homologue to a checkpoint kinase and is reportedly up-regulated in artemisinin-resistant parasites. Finally, we show that the cryptic checkpoint-kinase activity may also regulate the ring-stage survival phenotype after artemisinin damage, which resembles a G1/S checkpoint. Hence we suggest that checkpoint kinase inhibitors are candidates for synergy with artemisinin.