A divergent cyclin/cyclin-dependent kinase complex controls the atypical replication of a malaria parasite during gametogony and transmission.

Balestra, Aurélia C; Zeeshan, Mohammad; Rea, Edward; Pasquarello, Carla; Brusini, Lorenzo; Mourier, Tobias; Subudhi, Amit; Klages, Natacha; Arboit, Patrizia; Pandey, Rajan; Brady, Declan; Vaughan, Sue; Holder, Anthony A.; Pain, Arnab; Ferguson, David J P; Hainard, Alexandre; Tewari, Rita; Brochet, Mathieu

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KAUST Department

Biological and Environmental Sciences and Engineering (BESE) Division
Bioscience Program

KAUST Grant Number

BAS/1/1020-01-01

Date

2020-06-23

Submitted Date

2020-02-28

Permanent link to this record

http://hdl.handle.net/10754/663817

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Abstract

Cell cycle transitions are generally triggered by variation in the activity of cyclin-dependent kinases (CDKs) bound to cyclins. Malaria-causing parasites have a life cycle with unique cell-division cycles, and a repertoire of divergent CDKs and cyclins of poorly understood function and interdependency. We show that Plasmodium berghei CDK-related kinase 5 (CRK5), is a critical regulator of atypical mitosis in the gametogony and is required for mosquito transmission. It phosphorylates canonical CDK motifs of components in the pre-replicative complex and is essential for DNA replication. During a replicative cycle, CRK5 stably interacts with a single Plasmodium-specific cyclin (SOC2), although we obtained no evidence of SOC2 cycling by transcription, translation or degradation. Our results provide evidence that during Plasmodium male gametogony, this divergent cyclin/CDK pair fills the functional space of other eukaryotic cell-cycle kinases controlling DNA replication.

Citation

Balestra, A. C., Zeeshan, M., Rea, E., Pasquarello, C., Brusini, L., Mourier, T., … Brochet, M. (2020). A divergent cyclin/cyclin-dependent kinase complex controls the atypical replication of a malaria parasite during gametogony and transmission. eLife, 9. doi:10.7554/elife.56474

Sponsors

We thank Julie Rodger (Nottingham University) for her assistance in the insectary maintenance and Zineb Rchiad (KAUST) for RNAseq library preparation. We thank the excellent service at the bioimaging and flow-cytometry core facilities at the Faculty of Medicine of the University of Geneva. We also would like to thank Nisha Philip (University of Edinburgh) for sharing the 615 Tir1-expressing line as well as Wesley Van Voorhis and Kayode Ojo (University of Washington) for sharing compound BKI-1294. We thank Markus Ganter for sharing the reference GO term set used in this work. This work was supported by the Swiss National Science Foundation grant BSSGI0_155852 and 31003A_179321 to MB. MB is an INSERM and EMBO young investigator. The work in RT lab is supported by Medical Research Council UK (G0900109, G0900278, MR/K011782/1) and Biotechnology and Biological Sciences Research Council (BB/N017609/1). The work in AP lab is supported by a faculty baseline fund (BAS/1/1020-01-01) and a Competitive Research Grant (CRG) award from OSR (OSR-2018-CRG6-3392) from the King Abdullah University of Science and Technology. AAH was supported by the Francis Crick Institute (FC010097), which receives its core funding from Cancer Research UK (FC010097), the UK Medical Research Council (FC010097), and the Wellcome Trust (FC010097).

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