Checkpoints of apicomplexan cell division identified in Toxoplasma gondii

The unusual cell cycles of Apicomplexa parasites are remarkably flexible with the ability to complete cytokinesis and karyokinesis coordinately or postpone cytokinesis for several rounds of chromosome replication, and are well recognized. Despite this surprising biology, the molecular machinery requ...

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Bibliographic Details
Published in:PLoS pathogens 2017-07, Vol.13 (7), p.e1006483-e1006483
Main Authors: Alvarez, Carmelo A, Suvorova, Elena S
Format: Article
Language:English
Subjects:
Apicomplexa
Biology and Life Sciences
CDC2 Protein Kinase - genetics
CDC2 Protein Kinase - metabolism
Cell cycle
Cell Cycle Checkpoints
Cell Division
Chromosomes
Cyclins
Cyclins - genetics
Cyclins - metabolism
Cytokinesis
Division
Enzyme regulation
G1 phase
Genetic aspects
Health aspects
Kinases
Machinery
Mitosis
Molecular machines
Mutants
Parasites
Phosphotransferases
Protozoa
Protozoan Proteins - genetics
Protozoan Proteins - metabolism
Replication
Toxoplasma - cytology
Toxoplasma - genetics
Toxoplasma - growth & development
Toxoplasma - metabolism
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Summary:The unusual cell cycles of Apicomplexa parasites are remarkably flexible with the ability to complete cytokinesis and karyokinesis coordinately or postpone cytokinesis for several rounds of chromosome replication, and are well recognized. Despite this surprising biology, the molecular machinery required to achieve this flexibility is largely unknown. In this study, we provide comprehensive experimental evidence that apicomplexan parasites utilize multiple Cdk-related kinases (Crks) to coordinate cell division. We determined that Toxoplasma gondii encodes seven atypical P-, H-, Y- and L- type cyclins and ten Crks to regulate cellular processes. We generated and analyzed conditional tet-OFF mutants for seven TgCrks and four TgCyclins that are expressed in the tachyzoite stage. These experiments demonstrated that TgCrk1, TgCrk2, TgCrk4 and TgCrk6, were required or essential for tachyzoite growth revealing a remarkable number of Crk factors that are necessary for parasite replication. G1 phase arrest resulted from the loss of cytoplasmic TgCrk2 that interacted with a P-type cyclin demonstrating that an atypical mechanism controls half the T. gondii cell cycle. We showed that T. gondii employs at least three TgCrks to complete mitosis. Novel kinases, TgCrk6 and TgCrk4 were required for spindle function and centrosome duplication, respectively, while TgCrk1 and its partner TgCycL were essential for daughter bud assembly. Intriguingly, mitotic kinases TgCrk4 and TgCrk6 did not interact with any cyclin tested and were instead dynamically expressed during mitosis indicating they may not require a cyclin timing mechanism. Altogether, our findings demonstrate that apicomplexan parasites utilize distinctive and complex mechanisms to coordinate their novel replicative cycles.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1006483