Unravelling the role of Aurora kinases in cell cycle regulation of malaria parasites

Abstract

The P. falciparum parasite’s life cycle, and implied cell cycle, is strictly controlled allowing the parasite to rapidly develop during the intraerythrocytic stages alternating DNA synthesis and mitosis during endocyclic schizogony. This results in asynchronous nuclear divisions to form multinucleated schizonts during mitosis. However, mitotic nuclear division in P. falciparum parasites remain poorly understood. Several mitotic kinases of the P. falciparum kinome, such as aurora related kinases (ARKs), have been suggested to be cell cycle regulators. The PfARKs are essential for intraerythrocytic stages of the Plasmodium parasite of which PfARK-1 are highly conserved and associated with spindle pole bodies (SPB) during schizogony. The role of PfARK associated with SPB in cell cycle regulation of P. falciparum parasites has been understudied, despite the close link to centrosome and bipolar microtubule dynamics, chromosome segregation and cytokinesis of Aurora kinases in various other organisms. Knowledge gaps regarding the parasite’s cell cycle regulatory mechanisms is mostly due to the complexity associated with cell cycle compartment synchronisation of the parasite under in vitro conditions. In this dissertation, an innovative approach is used for cell cycle compartmentalisation of parasites as a tool to interrogate the importance of PfARK in cell cycle regulation during the intraerythrocytic stages of the parasite through hesperadin-induced PfARK inhibition. Collectively, this dissertation provides extensive insight to PfARK cell cycle regulation during parasite asynchronous nuclear division associated with M-phase progression, chromosomal segregation and spindle formation. The data demonstrate that novel cell cycle regulatory mechanisms of mitotic kinases, such as PfARKs and their involved pathways, serve as attractive future drug targets in Plasmodium parasites.