Abstract
Cell-cycle progression and cell division in eukaryotes are governed in part by the cyclin family and their regulation of cyclin-dependent kinases (CDKs). Cyclins are very well characterised in model systems such as yeast and human cells, but surprisingly little is known about their number and role in Plasmodium, the unicellular protozoan parasite that causes malaria. Malaria parasite cell division and proliferation differs from that of many eukaryotes. During its life cycle it undergoes two types of mitosis: endomitosis in asexual stages and an extremely rapid mitotic process during male gametogenesis. Both schizogony (producing merozoites) in host liver and red blood cells, and sporogony (producing sporozoites) in the mosquito vector, are endomitotic with repeated nuclear replication, without chromosome condensation, before cell division. The role of specific cyclins during Plasmodium cell proliferation was unknown. We show here that the Plasmodium genome contains only three cyclin genes, representing an unusual repertoire of cyclin classes. Expression and reverse genetic analyses of the single Plant (P)-type cyclin, CYC3, in the rodent malaria parasite, Plasmodium berghei, revealed a cytoplasmic and nuclear location of the GFP-tagged protein throughout the lifecycle. Deletion of cyc3 resulted in defects in size, number and growth of oocysts, with abnormalities in budding and sporozoite formation. Furthermore, global transcript analysis of the cyc3-deleted and wild type parasites at gametocyte and ookinete stages identified differentially expressed genes required for signalling, invasion and oocyst development. Collectively these data suggest that cyc3 modulates oocyst endomitotic development in Plasmodium berghei.
Highlights
The mechanisms of mitotic cell division and the various molecules involved are well studied in many model systems including yeast, plants and human cells
Atypical cell division occurs in oocysts, where repeated nuclear division precedes cell division, which gives rise to many sporozoites in a process known as sporogony
We show that CYC3 has a cytoplasmic and nuclear localisation throughout most of the parasite lifecycle and by gene deletion we demonstrate that CYC3 is important for normal oocyst development, maturation and sporozoite formation
Summary
The mechanisms of mitotic cell division and the various molecules involved are well studied in many model systems including yeast, plants and human cells. Progression through mitosis is controlled by a range of factors, including cyclins, protein kinases (PKs) and phosphatases (PPs), and the anaphase-promoting complex (APC) components [1,2,3,4]. Cyclins play active roles at distinct stages of the cell cycle [4] via regulation of cyclin-dependent kinases (CDKs). Cyclins possess a conserved ~100-residue sequence known as the cyclin box that mediates CDK binding and activation [5]. Certain cyclins are capable of binding several CDKs, which are themselves able to associate with multiple cyclins [6,7]. These distinct but overlapping functions orchestrate cell cycle progression
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