Cell cycle checkpoint activity in the malaria parasite Plasmodium falciparum
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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 orthologues 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.
Author summary
Malaria parasites cause illness by infecting human red blood cells, wherein they replicate to produce many new parasites within ∽1-3 days. This is unusual because most cells (such as human cells) replicate simply by copying their genome and splitting in half – which is called binary fission – but malaria parasites make ∽20 genome copies and then partition them simultaneously into 20 new cells – which is called schizogony. Here we studied how these parasites control schizogony. In particular, do they have ‘checkpoints’: the ability to pause the cell cycle for repair if the genome is damaged? We found that DNA damage during active replication did indeed cause hallmarks of a checkpoint. Key proteins that enforce this in other cells are surprisingly absent in malaria parasites, although DNA repair pathways and other regulatory pathways remain present. Furthermore, this checkpoint activity may be involved in the response to the antimalarial drug artemisinin: a response that parasites make by pausing their cycle before active replication begins. This could be important because it implies that inhibiting the checkpoint could exacerbate parasite killing by artemisinin-based drugs, similar to the way that some cancer therapies work by damaging DNA and also preventing the cancer cells from repairing it.
