Inducing controlled cell cycle arrest and re-entry during asexual proliferation of plasmodium falciparum malaria parasites

dc.contributor.authorVan Biljon, Riette Andele
dc.contributor.authorNiemand, Jandeli
dc.contributor.authorClark, Katherine
dc.contributor.authorVerlinden, Bianca K.
dc.contributor.authorAbrie, Clarissa
dc.contributor.authorVon Gruning, Hilde
dc.contributor.authorSmidt, Werner
dc.contributor.authorSmit, Annel
dc.contributor.authorReader, Janette
dc.contributor.authorPainter, Heather
dc.contributor.authorLlinas, Manuel
dc.contributor.authorDoerig, Christian
dc.contributor.authorBirkholtz, Lyn-Marie
dc.contributor.emaillbirkholtz@up.ac.zaen_ZA
dc.date.accessioned2019-07-01T12:38:47Z
dc.date.available2019-07-01T12:38:47Z
dc.date.issued2018-11-08
dc.description.abstractThe life cycle of the malaria parasite Plasmodium falciparum is tightly regulated, oscillating between stages of intense proliferation and quiescence. Cyclic 48-hour asexual replication of Plasmodium is markedly different from cell division in higher eukaryotes, and mechanistically poorly understood. Here, we report tight synchronisation of malaria parasites during the early phases of the cell cycle by exposure to DL-α-difluoromethylornithine (DFMO), which results in the depletion of polyamines. This induces an inescapable cell cycle arrest in G1 (~15 hours post-invasion) by blocking G1/S transition. Cell cycle-arrested parasites enter a quiescent G0-like state but, upon addition of exogenous polyamines, re-initiate their cell cycle. This ability to halt malaria parasites at a specific point in their cell cycle, and to subsequently trigger re-entry into the cell cycle, provides a valuable framework to investigate cell cycle regulation in these parasites. We subsequently used gene expression analyses to show that re-entry into the cell cycle involves expression of Ca2+-sensitive (cdpk4 and pk2) and mitotic kinases (nima and ark2), with deregulation of the pre-replicative complex associated with expression of pk2. Changes in gene expression could be driven through transcription factors MYB1 and two ApiAP2 family members. This new approach to parasite synchronisation therefore expands our currently limited toolkit to investigate cell cycle regulation in malaria parasites.en_ZA
dc.description.departmentBiochemistryen_ZA
dc.description.departmentGeneticsen_ZA
dc.description.departmentMicrobiology and Plant Pathologyen_ZA
dc.description.librarianam2019en_ZA
dc.description.sponsorshipGrants from the South African National Research Foundation (UID 84627) and the European Commission ‘EviMalar” (ref 242095) to LMB. JN was supported by grants from the Claude Leon Foundation. LMB and JN acknowledge the South African Medical Research Council (MRC) for funding the University of Pretoria Institute for Sustainable Malaria Control as MRC Collaborating Centre for malaria research.en_ZA
dc.description.urihttp://www.nature.com/srepen_ZA
dc.identifier.citationVan Biljon, R., Niemand, J., Van Wyk, R. et al. 2018, 'Inducing controlled cell cycle arrest and re-entry during asexual proliferation of plasmodium falciparum malaria parasites', Scientific Reports, vol. 8, art. 16581, pp. 1-14.en_ZA
dc.identifier.issn2045-2322 (online)
dc.identifier.other10.1038/s41598-018-34964-w
dc.identifier.urihttp://hdl.handle.net/2263/70337
dc.language.isoenen_ZA
dc.publisherNature Publishing Groupen_ZA
dc.rights© The Author(s) 2018. This article is licensed under a Creative Commons Attribution 4.0 International License.en_ZA
dc.subjectPlasmodium falciparumen_ZA
dc.subjectPolyaminesen_ZA
dc.subjectSynchronisationen_ZA
dc.subjectMalaria parasitesen_ZA
dc.subjectCell cycle progressionen_ZA
dc.subjectDL-α-difluoromethylornithine (DFMO)en_ZA
dc.subjectDepletion of polyaminesen_ZA
dc.titleInducing controlled cell cycle arrest and re-entry during asexual proliferation of plasmodium falciparum malaria parasitesen_ZA
dc.typeArticleen_ZA

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