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A divergent cyclin/cyclin-dependent kinase complex controls progression through the atypical replicative cycles during Plasmodium berghei gametogony

ABSTRACT: Cell-cycle transitions are generally triggered by variations in the activity of cyclin-dependent kinases (CDKs) bound to cyclins. Malaria-causing parasites have evolved unique cell-cycles with a repertoire of ancestral CDKs and cyclins whose functions and interdependency remain elusive. Here, we show that the divergent Plasmodium berghei CDK-related kinase 5 (CRK5), is a critical cell-cycle regulator of gametogony required for transmission to the mosquito. It phosphorylates canonical CDK motifs on components of the pre-replicative complex and is essential for DNA replication. We also provide evidence for indirect regulation of the concomitant progression through M-phase. Over a replicative cycle, CRK5 stably interacts with a single Plasmodium-specific cyclin (SOC2) with no evidence of SOC2 cycling through transcription, translation nor degradation. Our results present evidence that during Plasmodium gametogony, a unique and divergent cyclin/CDK pair evolved to fulfil the functional space of multiple eukaryotic cell-cycle kinases controlling S-phase entry and progression through M-phase.

ORGANISM(S): Plasmodium berghei

PROVIDER: GSE144743 | GEO | 2020/06/17

REPOSITORIES: GEO

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A divergent cyclin/cyclin-dependent kinase complex controls progression through the atypical replicative cycles during Plasmodium berghei gametogony

Project description:Cell-cycle transitions are generally triggered by variations in the activity of cyclin-dependent kinases (CDKs) bound to cyclins. Malaria-causing parasites have evolved unique cell-cycles with a repertoire of ancestral CDKs and cyclins whose functions and interdependency remain elusive. Here, we show that the divergent Plasmodium berghei CDK-related kinase 5 (CRK5), is a critical cell-cycle regulator of gametogony required for transmission to the mosquito. It phosphorylates canonical CDK motifs on components of the pre-replicative complex and is essential for DNA replication. We also provide evidence for indirect regulation of the concomitant progression through M-phase. Over a replicative cycle, CRK5 stably interacts with a single Plasmodium-specific cyclin (SOC2) with no evidence of SOC2 cycling through transcription, translation nor degradation. Our results present evidence that during Plasmodium gametogony, a unique and divergent cyclin/CDK pair evolved to fulfil the functional space of multiple eukaryotic cell-cycle kinases controlling S-phase entry and progression through M-phase.

2020-02-25 | PXD017308 | Pride

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

Project description: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. We also provide evidence for indirect regulation of the concomitant M-phase progression. 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 unique cyclin/CDK pair fills the functional space of multiple eukaryotic cell-cycle kinases controlling DNA replication and M-phase progression.

2020-06-17 | PXD017622 | Pride

A unique and divergent cyclin/cyclin-dependent kinase complex controls DNA replication during atypical cell-cycles of Plasmodium berghei gametogonyA unique and divergent cyclin/cyclin-dependent kinase complex controls DNA replication during atypical cell-cycles of Plasmodium berghei gametogony

Project description:Cell-cycle transitions are generally triggered by variations in the activity of cyclin-dependent kinases (CDKs) bound to cyclins. Malaria parasites express ancestral CDKs and cyclins, whose functions and interdependency remain elusive. Here, we show that the unique Plasmodium berghei CDK-related kinase 5 (CRK5), is a critical cell-cycle regulator of gametogony required for transmission to the mosquito. It is essential for DNA replication and phosphorylates canonical S/TPxK CDK motifs on components of the pre-replicative complex otherwise regulated by distinct kinases in other eukaryotes. Over a replicative cycle, CRK5 stably interacts with a single Haemosporidia-specific cyclin (SOC2) with no evidence of SOC2 degradation. Regulation of CRK5 activity relies instead on dynamic phosphorylation of a C-terminus extension that mediates its interaction with SOC2. Our results present evidence that during the atypical cell cycles of Plasmodium gametogony, a unique and divergent cyclin/CDK pair fulfils the functional space of multiple eukaryotic cell-cycle kinases to initiate DNA replication.

2020-02-18 | PXD017283 | Pride

Redundancy and Specialisation of Cyclin Dependent Kinases

Project description:Cyclin dependent kinases (CDKs) lie at the heart of eukaryotic cell division, with different CDK complexes initiating DNA replication (S-CDKs) and mitosis (M-CDKs)1-3. However, the principles on which cyclin-CDKs organise the cell cycle are still contentious, with current theories suggesting that either M-CDKs and S-CDKs are redundant with each other, and simply serve as a source of CDK activity, or that they are functionally specialised and execute distinct tasks. Here we reconcile these two views, showing that although S-CDKs are unable to drive mitosis, global CDK phosphorylation in vivo between S-CDK and M-CDK is surprisingly similar. Remarkably, S-CDK has cryptic mitotic activity which can be exposed by the removal of Protein Phosphatase 1 (PP1). In particular, removal of centrosomal PP1 allows S-CDK to execute mitosis indistinguishably from M-CDK, demonstrating their functional redundancy. Thus, we reconcile the two opposing views of cell cycle control, showing that although there is a minor level of specialisation between S-CDKs and M-CDKs, that the core cell cycle engine is based upon modulation of CDK activity, with cyclins providing refinements to this core system.

2022-03-22 | PXD029073 | Pride

Transcription profiling of S. cerevisiae wild type and cyclin mutant

Project description:Yeast cell cycle transcription dynamics in two S. cerevisae strains: BF264-15DU (MATa ade1 his2 leu2-3, 112 trp1-1 ura3Dns, bar1) [referred to as wild type] and a mutant of the wild type strain, clb1,2,3,4,5,6 GAL1-CLB1, [referred to as cyclin mutant] that does not express S-phase and mitotic cyclins. Both strains were synchronized by elutriation and released into YEP 2% dextrose/1M sorbitol at 30c. 15 samples were taken at 16 min intervals covering ~2 cycles in wild-type and ~1.5 cycles for the mutants. A significant fraction of the Saccharomyces cerevisiae genome is transcribed periodically during the cell division cycle, suggesting that properly timed gene expression is important for regulating cell cycle events. Genomic analyses of transcription factor localization and expression dynamics suggest that a network of sequentially expressed transcription factors could control the temporal program of transcription during the cell cycle. However, directed studies interrogating small numbers of genes indicate that their periodic transcription is governed by the activity of cyclin-dependent kinases (CDKs). To determine the extent to which the global cell cycle transcription program is controlled by cyclin/CDK complexes, we compared genome-wide transcription dynamics in wild type budding yeast to mutants that do not express S-phase and mitotic cyclins. Experiment Overall Design: Cell cycle synchrony/time series experiments. G1 cells collected by elutriation was examined over time for 2 cell cycles. Strains compared: wild type vs cyclin mutants. 15 samples per time course at 16 min resolution. 2 biological replicates per strain.

2008-06-20 | E-GEOD-8799 | biostudies-arrayexpress

Budding yeast relies on qualitative G1 cyclin specificity to couple cell cycle progression with morphogenetic development

Project description:Two models have been put forward for cyclin-dependent kinase (Cdk) control of the cell cycle. In the qualitative model, cell cycle events are ordered by distinct substrate specificities associated with successive waves of G1, S and mitotic cyclins. Alternatively, the gradual quantitative rise of Cdk activity from G1 phase to mitosis could lead to ordered substrate phosphorylation at sequential thresholds. Here, we study the relative contributions of qualitative and quantitative Cdk control in the budding yeast S. cerevisiae. S-phase cyclins can be replaced by a single mitotic cyclin, albeit at the cost of reduced fitness. The single cyclin can in addition replace G1 cyclins to support ordered cell cycle progression, fulfilling key predictions of the quantitative model. However, single-cyclin cells fail to polarize or grow buds and thus cannot sustain proliferation. Our results suggest that budding yeast has become dependent on G1 cyclin specificity to couple cell cycle progression to essential morphogenetic events.

2021-08-23 | PXD022757 | Pride

Cyclin-dependant kinase (CDK) orders the cell cycle via substrate specific thresholds

Project description:The appropriate ordering of the cell cycle events in eukaryoates is thought to be brought about by qualitative differences in the substrate specificity of multiple differentially expression Cyclin-CDK complexes. Our analysis of fission yeast supports an alternative quantitative model. Here we report a phosphoproteomics based global analysis of CDK substrate phosphorylation. We show that the phosphorylation of different CDK substrates is precisely ordered during the cell cycle by a single Cyclin-CDK complex. This is achieved by the differential sensitivity of substrates to a progressively rising CDK-to-phosphatase activity ratio, with early-phosphorylated substrates more sensitive to CDK activity than late substrates. This is combined with a rapid substrate phosphorylation turnover to generate clearly resolved substrate-specific thresholds, which in turn ensures the temporal ordering of downstream cell cycle events. These observations can also explain the major genetic redundancies between different cyclins and CDKs in higher eukaryotes.

2018-04-11 | PXD003598 | Pride

CDK activity at the centrosome regulates the cell cycle

Project description:Cyclin-dependent kinases (CDKs) complexed with cyclins drive progression through the eukaryotic cell cycle. From yeast to human cells, cyclin-CDK localises to the centrosome, but the importance of this localisation is unclear. The conserved ‘hydrophobic patch’ substrate docking site on human Cyclin B1 and on the equivalent fission yeast Cdc13 mediates their localisation to the centrosome and the spindle-pole body (SPB, yeast centrosome equivalent). A hydrophobic patch mutant (HPM) of Cdc13 cannot enter mitosis, but whether this mitotic defect is due to defective SPB localisation or defective cyclin-substrate docking is unknown. Here we show that artificially restoring Cdc13HPM SPB localisation in fission yeast partially rescues both mitosis and defective CDK substrate phosphorylation at both the SPB and within the cytoplasm. In addition, we found that an HPM of the S-phase cyclin Cig2 has defective SPB localisation but is still able to perform bulk DNA synthesis. Our results demonstrate that the hydrophobic patch mediates the SPB localisation of both S- and M-phase cyclins, and that Cdc13 SPB localisation is essential for mitotic entry and for full phosphorylation of CDK substrates, supporting the view that the centrosome plays a role as a signalling hub regulating CDK cell cycle control.

2024-04-04 | PXD044732 | Pride

Gradual evolution of cell cycle regulation by cyclin-dependant kinases during the transition to animal multicellularity

Project description:We assessed temporal gene expression in synchronous cultures of Capsaspora owczarzaki in order to better understand cell cycle regulation in another opisthokont more closely related to animals retaining the ancestral toolkit of cell cycle regulators. Our data suggests that cell cycle regulation in the ancestor of Capsaspora and animals involved one single CDK binding to multiple cyclins of subfamilies in the same temporal order as in animals, and that expansion of CDKs occured later in the lineage that gave rise to animals.

2020-01-04 | GSE141156 | GEO

Global Control of cell cycle transcription by coupled CDK and network oscillators

2008-05-07 | GSE8799 | GEO

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