Apicomplexa Cell Cycles: Something Old, Borrowed, Lost, and New
2018; Elsevier BV; Volume: 34; Issue: 9 Linguagem: Inglês
10.1016/j.pt.2018.07.006
ISSN1471-5007
AutoresMichael W. White, Elena S. Suvorova,
Tópico(s)Microbial infections and disease research
ResumoDo Apicomplexa cell cycles represent a new paradigm? Compared to other eukaryotes (yeast and mammals), images of dividing Apicomplexa parasites might suggest so. Yet, new comparative genomics and morphogenic research tells a different story of ancient and borrowed features adapted to yield new parasites. The T. gondii bipartite centrosome with functionally independent inner and outer cores provides a new molecular logic for flexible nuclear cycles. Aurora, Nek, Crk kinases and E3 ligase tethered to T. gondii mitotic structures provides evidence for local nuclear control, which is needed to explain the apparent violation of 'copy once rules' in multinuclear replication. If there is a new paradigm it is the suspension of concerted budding until the last nuclear cycle. Here there are new data for greater Crk complexity that has been freed from requiring a cyclin partner. Increased parasite burden is linked to the severity of clinical disease caused by Apicomplexa parasites such as Toxoplasma gondii, Plasmodium spp, and Cryptosporidium. Pathogenesis of apicomplexan infections is greatly affected by the growth rate of the parasite asexual stages. This review discusses recent advances in deciphering the mitotic structures and cell cycle regulatory factors required by Apicomplexa parasites to replicate. As the molecular details become clearer, it is evident that the highly unconventional cell cycles of these parasites is a blending of many ancient and borrowed elements, which were then adapted to enable apicomplexan proliferation in a wide variety of different animal hosts. Increased parasite burden is linked to the severity of clinical disease caused by Apicomplexa parasites such as Toxoplasma gondii, Plasmodium spp, and Cryptosporidium. Pathogenesis of apicomplexan infections is greatly affected by the growth rate of the parasite asexual stages. This review discusses recent advances in deciphering the mitotic structures and cell cycle regulatory factors required by Apicomplexa parasites to replicate. As the molecular details become clearer, it is evident that the highly unconventional cell cycles of these parasites is a blending of many ancient and borrowed elements, which were then adapted to enable apicomplexan proliferation in a wide variety of different animal hosts. Papers and reviews describing asexual cell division of apicomplexans often use many wonder type adjectives such as unusual, peculiar, unprecedented, and remarkable (we are guilty as charged). The problem with our collective habit is that it effectively treats these protozoans as aliens on Earth and inevitably misses compelling biological backstories and what is truly unique about these important pathogens. The Old English Rhyme,'Something old,Something new,Something borrowed, andSomething blue', that describes the essential ingredients of marriage does a much better job of portraying the melding of processes that together produce apicomplexan biology (using an alternative meaning of blue – 'lost'). In this review, we focus on recent advances in understanding the structural and molecular basis of cell division in the model apicomplexan, T. gondii, placing where possible new discoveries in an evolutionary context. Our strategy for evaluating evolutionary contexts is to assume new is rare, look for old first in genomics and cell biological evidence. We then assess whether the trait is borrowed from algae or plants. We keep in mind that often pathway topology may be conserved while individual protein elements are not, which especially applies to cell cycle regulatory networks [1Cross F.R. et al.Evolution of networks and sequences in eukaryotic cell cycle control.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2011; 366: 3532-3544Crossref PubMed Scopus (106) Google Scholar]. At the dawn of the Apicomplexa lineage divergence, several hundred million years had likely passed since the emergence of the last common ancestor of eukaryote, LECA (see Glossary) [2Cavalier-Smith T. Kingdom protozoa and its 18 phyla.Microbiol. Rev. 1993; 57: 953-994Crossref PubMed Google Scholar] (Figure 1A and Box 1). The ancestor of apicomplexans is thought to be similar to the present-day free-living phototrophic algae [3Woo Y.H. et al.Chromerid genomes reveal the evolutionary path from photosynthetic algae to obligate intracellular parasites.eLife. 2015; 4e06974Crossref PubMed Scopus (137) Google Scholar] and is dated to the beginning or later than the emergence of the Archaeplastida plant lineages based on the plastid organelle acquired by secondary endosymbiosis of a red alga [4Stiller J.W. Hall B.D. The origin of red algae: implications for plastid evolution.Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 4520-4525Crossref PubMed Scopus (290) Google Scholar, 5Adl S.M. et al.The revised classification of eukaryotes.J. Eukaryot. Microbiol. 2012; 59: 429-493Crossref PubMed Scopus (1171) Google Scholar] (Figure 1A). The driving force of subsequent Apicomplexa lineage divergence is the complete switch to a parasitic life style, and this led to significant reductions of genetic content [3Woo Y.H. et al.Chromerid genomes reveal the evolutionary path from photosynthetic algae to obligate intracellular parasites.eLife. 2015; 4e06974Crossref PubMed Scopus (137) Google Scholar]. It is estimated that >4000 orthologous genes in the proto-apicomplexan ancestor were lost in some apicomplexan lineages. The proteins lost [3Woo Y.H. et al.Chromerid genomes reveal the evolutionary path from photosynthetic algae to obligate intracellular parasites.eLife. 2015; 4e06974Crossref PubMed Scopus (137) Google Scholar] include flagella proteins and those needed for photosynthesis and some scavenging processes. In other words, if it were needed for a free-living life style it might not be present in extant apicomplexans. As predictable as gene losses are, the small gains in gene function also make sense. Secretory proteins needed to invade and survive within a host, and a new motility apparatus adapted to a multilayered cytoskeleton, highlight the functions gained during Apicomplexa phylum evolution.Box 1The Surprising Complexity of the LECAThe first organism on Earth was a prokaryote that emerged ∼3.5 billion years ago, and this type of cell dominated life for several billion years [73Cavalier-Smith T. Predation and eukaryote cell origins: a coevolutionary perspective.Int. J. Biochem. Cell. Biol. 2009; 41: 307-322Crossref PubMed Scopus (133) Google Scholar]. Eukaryotes were thought to have appeared within the marine environment 800–1500 million years ago [2Cavalier-Smith T. Kingdom protozoa and its 18 phyla.Microbiol. Rev. 1993; 57: 953-994Crossref PubMed Google Scholar, 73Cavalier-Smith T. Predation and eukaryote cell origins: a coevolutionary perspective.Int. J. Biochem. Cell. Biol. 2009; 41: 307-322Crossref PubMed Scopus (133) Google Scholar, 74Cavalier-Smith T. Kingdom Chromista and its eight phyla: a new synthesis emphasising periplastid protein targeting, cytoskeletal and periplastid evolution, and ancient divergences.Protoplasma. 2018; 255: 297-357Crossref PubMed Scopus (83) Google Scholar, 75de Vries J. Gould S.B. The monoplastidic bottleneck in algae and plant evolution.J. Cell Sci. 2018; 131Crossref PubMed Scopus (32) Google Scholar, 76Koumandou V.L. et al.Molecular paleontology and complexity in the last eukaryotic common ancestor.Crit. Rev. Biochem. Mol. Biol. 2013; 48: 373-396Crossref PubMed Scopus (128) Google Scholar], and it is proposed that dozens of new innovations in the last common ancestor of eukaryotes (LECA) were required to establish the eukaryotic lineage [73Cavalier-Smith T. Predation and eukaryote cell origins: a coevolutionary perspective.Int. J. Biochem. Cell. Biol. 2009; 41: 307-322Crossref PubMed Scopus (133) Google Scholar, 76Koumandou V.L. et al.Molecular paleontology and complexity in the last eukaryotic common ancestor.Crit. Rev. Biochem. Mol. Biol. 2013; 48: 373-396Crossref PubMed Scopus (128) Google Scholar]. First innovations required other innovations leading to yet more innovations and so on. For example, the packaging of eukaryotic chromosomes (histone-nucleosomes) into chromatin eliminated the size restrictions that have governed bacterial chromosomes throughout their history [77Omodeo O.P. The biggest evolutionary jump: restructuring of the genome and some consequences.Tsitologiia. 2010; 52: 797-816PubMed Google Scholar] and permitted the nascent eukaryote genome to quickly expand with the addition of hundreds of new genes and paralogs [63Iyer L.M. et al.Comparative genomics of transcription factors and chromatin proteins in parasitic protists and other eukaryotes.Int. J. Parasitol. 2008; 38: 1-31Crossref PubMed Scopus (201) Google Scholar]. Nuclear compartmentalization of chromosomes required a new type of replication called mitosis, and the separation of gene transcription and translation led to new processes for producing mature mRNA and ribosomes. Nuclear developments also required the development of pores and new transport mechanisms. The take-home message of this brief summary is that the first eukaryote cell was likely more complex than some modern eukaryotes and not nearly as primitive as commonly assumed. This new conceptual view of the LECA is extensively discussed in two recent reviews [73Cavalier-Smith T. Predation and eukaryote cell origins: a coevolutionary perspective.Int. J. Biochem. Cell. Biol. 2009; 41: 307-322Crossref PubMed Scopus (133) Google Scholar, 76Koumandou V.L. et al.Molecular paleontology and complexity in the last eukaryotic common ancestor.Crit. Rev. Biochem. Mol. Biol. 2013; 48: 373-396Crossref PubMed Scopus (128) Google Scholar]. The first organism on Earth was a prokaryote that emerged ∼3.5 billion years ago, and this type of cell dominated life for several billion years [73Cavalier-Smith T. Predation and eukaryote cell origins: a coevolutionary perspective.Int. J. Biochem. Cell. Biol. 2009; 41: 307-322Crossref PubMed Scopus (133) Google Scholar]. Eukaryotes were thought to have appeared within the marine environment 800–1500 million years ago [2Cavalier-Smith T. Kingdom protozoa and its 18 phyla.Microbiol. Rev. 1993; 57: 953-994Crossref PubMed Google Scholar, 73Cavalier-Smith T. Predation and eukaryote cell origins: a coevolutionary perspective.Int. J. Biochem. Cell. Biol. 2009; 41: 307-322Crossref PubMed Scopus (133) Google Scholar, 74Cavalier-Smith T. Kingdom Chromista and its eight phyla: a new synthesis emphasising periplastid protein targeting, cytoskeletal and periplastid evolution, and ancient divergences.Protoplasma. 2018; 255: 297-357Crossref PubMed Scopus (83) Google Scholar, 75de Vries J. Gould S.B. The monoplastidic bottleneck in algae and plant evolution.J. Cell Sci. 2018; 131Crossref PubMed Scopus (32) Google Scholar, 76Koumandou V.L. et al.Molecular paleontology and complexity in the last eukaryotic common ancestor.Crit. Rev. Biochem. Mol. Biol. 2013; 48: 373-396Crossref PubMed Scopus (128) Google Scholar], and it is proposed that dozens of new innovations in the last common ancestor of eukaryotes (LECA) were required to establish the eukaryotic lineage [73Cavalier-Smith T. Predation and eukaryote cell origins: a coevolutionary perspective.Int. J. Biochem. Cell. Biol. 2009; 41: 307-322Crossref PubMed Scopus (133) Google Scholar, 76Koumandou V.L. et al.Molecular paleontology and complexity in the last eukaryotic common ancestor.Crit. Rev. Biochem. Mol. Biol. 2013; 48: 373-396Crossref PubMed Scopus (128) Google Scholar]. First innovations required other innovations leading to yet more innovations and so on. For example, the packaging of eukaryotic chromosomes (histone-nucleosomes) into chromatin eliminated the size restrictions that have governed bacterial chromosomes throughout their history [77Omodeo O.P. The biggest evolutionary jump: restructuring of the genome and some consequences.Tsitologiia. 2010; 52: 797-816PubMed Google Scholar] and permitted the nascent eukaryote genome to quickly expand with the addition of hundreds of new genes and paralogs [63Iyer L.M. et al.Comparative genomics of transcription factors and chromatin proteins in parasitic protists and other eukaryotes.Int. J. Parasitol. 2008; 38: 1-31Crossref PubMed Scopus (201) Google Scholar]. Nuclear compartmentalization of chromosomes required a new type of replication called mitosis, and the separation of gene transcription and translation led to new processes for producing mature mRNA and ribosomes. Nuclear developments also required the development of pores and new transport mechanisms. The take-home message of this brief summary is that the first eukaryote cell was likely more complex than some modern eukaryotes and not nearly as primitive as commonly assumed. This new conceptual view of the LECA is extensively discussed in two recent reviews [73Cavalier-Smith T. Predation and eukaryote cell origins: a coevolutionary perspective.Int. J. Biochem. Cell. Biol. 2009; 41: 307-322Crossref PubMed Scopus (133) Google Scholar, 76Koumandou V.L. et al.Molecular paleontology and complexity in the last eukaryotic common ancestor.Crit. Rev. Biochem. Mol. Biol. 2013; 48: 373-396Crossref PubMed Scopus (128) Google Scholar]. All apicomplexan life cycles have two basic objectives, to produce sufficient progeny to perpetuate existence and to form the specialized stages needed for successful host transmission. Asexual stages are responsible for meeting the biotic mass requirements. Thus, replication terminology is based on where new parasites are formed; when daughter parasites are formed internally the process is called endodyogeny/endopolygeny, while budding from the mother plasmalemma is called schizogony [6Ferguson D.J. et al.MORN1 has a conserved role in asexual and sexual development across the apicomplexa.Eukaryot. Cell. 2008; 7: 698-711Crossref PubMed Scopus (78) Google Scholar]. The binary replication of the Toxoplasma tachyzoite is the simplest proliferative scale as most apicomplexan cell divisions produce more than two nuclei with concerted budding accompanying the last nuclear reduplication (Figure 2). Multinuclear replication is not a parasitic trait, because many free-living eukaryotes utilize this strategy, including the nearest free-living relatives of the Apicomplexa, chromerids [7Fussy Z. et al.Budding of the alveolate alga Vitrella brassicaformis resembles sexual and asexual processes in apicomplexan parasites.Protist. 2017; 168: 80-91Crossref PubMed Scopus (13) Google Scholar, 8Janouskovec J. et al.Factors mediating plastid dependency and the origins of parasitism in apicomplexans and their close relatives.Proc. Natl. Acad. Sci. U. S. A. 2015; 112: 10200-10207Crossref PubMed Scopus (126) Google Scholar]. The switch to a parasitic lifestyle may be responsible for the extraordinary scales and the near universal adoption of this type of replication in apicomplexan parasites. Cell division in Toxoplasma tachyzoites is founded on a number of ancestral mechanisms, especially those processes for copying (S phase) and segregating (mitosis) chromosomes (Figure 2). Present apicomplexans possess the core DNA synthetic machinery conserved across eukaryote domains, including all subunits of the MCM helicase complex and functionally specialized DNA polymerases [9Matthews H. et al.Checks and balances? DNA replication and the cell cycle in Plasmodium.Parasit. Vectors. 2018; 11: 216Crossref PubMed Scopus (43) Google Scholar, 10Naumov A. et al.The Toxoplasma centrocone houses cell cycle regulatory factors.mBio. 2017; 8Crossref PubMed Scopus (19) Google Scholar] (Figure 3 and Box 2). Key factors that direct the DNA synthetic machinery to specific initiation sites in the chromosomes are also present [9Matthews H. et al.Checks and balances? DNA replication and the cell cycle in Plasmodium.Parasit. Vectors. 2018; 11: 216Crossref PubMed Scopus (43) Google Scholar]. The sequences of the origins of DNA replication (ori) that have been recently mapped in Plasmodium falciparum appear to be similar to those in yeast [11Agarwal M. et al.Identification and characterization of ARS-like sequences as putative origin(s) of replication in human malaria parasite Plasmodium falciparum.FEBS J. 2017; 284: 2674-2695Crossref PubMed Scopus (8) Google Scholar]. There are differences noted in some of these DNA synthetic mechanisms, mostly as the result of gene loss [9Matthews H. et al.Checks and balances? DNA replication and the cell cycle in Plasmodium.Parasit. Vectors. 2018; 11: 216Crossref PubMed Scopus (43) Google Scholar, 10Naumov A. et al.The Toxoplasma centrocone houses cell cycle regulatory factors.mBio. 2017; 8Crossref PubMed Scopus (19) Google Scholar]. The apicomplexans have conserved the kinetochore proteins and the histone CenH3 that specifically binds centromeres [12Rout M.P. et al.Specialising the parasite nucleus: Pores, lamins, chromatin, and diversity.PLoS Pathog. 2017; 13e1006170Crossref PubMed Scopus (9) Google Scholar]. Thus, chromosome spindle attachment mechanisms in Toxoplasma also belong in the 'old' category. Tachyzoite intranuclear spindles are typically short, but can span the 1–2 μm nucleus [13Suvorova E.S. et al.A novel bipartite centrosome coordinates the apicomplexan cell cycle.PLoS Biol. 2015; 13e1002093Crossref PubMed Scopus (68) Google Scholar, 14Chen C.T. et al.Compartmentalized Toxoplasma EB1 bundles spindle microtubules to secure accurate chromosome segregation.Mol. Biol. Cell. 2015; 26: 4562-4576Crossref PubMed Google Scholar]. Centromeres are clustered and bound to the nuclear membrane near the spindle pole in all cell cycle phases except mitosis (spindle forms in mitosis only) [15Brooks C.F. et al.Toxoplasma gondii sequesters centromeres to a specific nuclear region throughout the cell cycle.Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 3767-3772Crossref PubMed Scopus (78) Google Scholar, 16Francia M.E. Striepen B. Cell division in apicomplexan parasites.Nat. Rev. Microbiol. 2014; 12: 125-136Crossref PubMed Scopus (156) Google Scholar]. This structural arrangement likely involves apicomplexan contributions. However, as a strategy, chromosome clustering near the spindle pole throughout the cell cycle is observed in many unicellular eukaryotes [17Drechsler H. McAinsh A.D. Exotic mitotic mechanisms.Open Biol. 2012; 2 (120140)Crossref PubMed Scopus (34) Google Scholar], and this feature permits the unikont fission yeast to complete nuclear division in the absence of a spindle [18Castagnetti S. et al.Fission yeast cells undergo nuclear division in the absence of spindle microtubules.PLoS Biol. 2010; 8e1000512Crossref PubMed Scopus (38) Google Scholar].Box 2Conventional versus Apicomplexan Cell CycleG1 PhaseThe apicomplexan G1 phase may be initiated by sensing and transducing environmental signals via the activity of signaling kinases [78Brown K.M. et al.Plasma membrane association by N-acylation governs PKG function in Toxoplasma gondii.mBio. 2017; 8Crossref Scopus (80) Google Scholar, 79Lourido S. et al.Distinct signalling pathways control Toxoplasma egress and host-cell invasion.EMBO J. 2012; 31: 4524-4534Crossref PubMed Scopus (142) Google Scholar], which triggers an ordered biosynthetic cascade [39Behnke M.S. et al.Coordinated progression through two subtranscriptomes underlies the tachyzoite cycle of Toxoplasma gondii.PLoS One. 2010; 5e12354Crossref PubMed Scopus (185) Google Scholar, 80Bozdech Z. et al.The transcriptome of the intraerythrocytic developmental cycle of Plasmodium falciparum.PLoS Biol. 2003; 1: E5Crossref PubMed Scopus (1260) Google Scholar]. The G1 checkpoint mechanism is an atypical G1 kinase Crk2 in complex with a P/U-cyclin. Typical of eukaryotic G1 topology, low Crk2 activity in Toxoplasma gondii associates with G1 arrest, which is likely equivalent to eukaryotic Restriction or START-like checkpoints ('old'). Traditional immediate G1 effectors of E2F/DP-1/Rb (or SBF/Whi5) families are 'lost' in many Apicomplexa genomes and are possibly replaced ('borrowed') with the ApiAP2 family of transcriptional factors that were acquired from the red alga symbiont.S PhaseApicomplexan S phase has a DNA synthesis checkpoint that controls two processes: DNA damage is regulated by the inherited ('old') ATM kinase [81Vonlaufen N. et al.MYST family lysine acetyltransferase facilitates ataxia telangiectasia mutated (ATM) kinase-mediated DNA damage response in Toxoplasma gondii.J. Biol. Chem. 2010; 285: 11154-11161Crossref PubMed Scopus (29) Google Scholar], while licensing of DNA replication is likely regulated by the 'new' kinase Crk5 [10Naumov A. et al.The Toxoplasma centrocone houses cell cycle regulatory factors.mBio. 2017; 8Crossref PubMed Scopus (19) Google Scholar]. DNA-replication machinery operated by novel Crk5 (ORC/Mcm) is 'old' and nearly complete [9Matthews H. et al.Checks and balances? DNA replication and the cell cycle in Plasmodium.Parasit. Vectors. 2018; 11: 216Crossref PubMed Scopus (43) Google Scholar]. Surprisingly, the oldest ancestral checkpoint kinase Chk1 that connects G1, S phase and mitosis is missing in apicomplexans and chromerids along with factors from the Chk1 network, which supports the concept that coevolved complexes are preserved or lost as a unit [62de Lichtenberg U. et al.Evolution of cell cycle control: Same molecular machines, different regulation.Cell Cycle. 2007; 6: 1819-1825Crossref PubMed Scopus (27) Google Scholar]. Please note that conventional cell cycle has an additional DNA damage/replication checkpoint in the G2 phase that is likely lost in apicomplexans due to the absence of a detectable G2 period and associated regulators, such as Cdc25a phosphatase (see Figure 3 in main text).MitosisMitosis in apicomplexan cell division has retained many 'old' components of the primordial cell cycle. Duplication and segregation of MTOC (centrosome or centrosomal plaque) that establishes spindle poles for chromosome segregation is similarly regulated by serine/threonine protein kinases of Nek and Aurora families [9Matthews H. et al.Checks and balances? DNA replication and the cell cycle in Plasmodium.Parasit. Vectors. 2018; 11: 216Crossref PubMed Scopus (43) Google Scholar, 13Suvorova E.S. et al.A novel bipartite centrosome coordinates the apicomplexan cell cycle.PLoS Biol. 2015; 13e1002093Crossref PubMed Scopus (68) Google Scholar, 34Chen C.T. Gubbels M.J. The Toxoplasma gondii centrosome is the platform for internal daughter budding as revealed by a Nek1 kinase mutant.J. Cell Sci. 2013; 126: 3344-3355Crossref PubMed Scopus (43) Google Scholar, 82Berry L. et al.The conserved apicomplexan Aurora kinase TgArk3 is involved in endodyogeny, duplication rate and parasite virulence.Cell. Microbiol. 2016; 18: 1106-1120Crossref PubMed Scopus (23) Google Scholar, 83Carvalho T.G. et al.Nima- and Aurora-related kinases of malaria parasites.Biochim. Biophys. Acta. 2013; 1834: 1336-1345Crossref PubMed Scopus (36) Google Scholar], while polo-like kinases (PLKs) are 'lost' in apicomplexans and ancestral chromerids. Similar to canonical spindle-assembly checkpoint (SAC), apicomplexan parasites regulate metaphase-to-anaphase transition. While many components of the SAC network are preserved in apicomplexans ('old': MCC – mitotic checkpoint complex, APC/C – anaphase-promoting complex/cyclosome) [72Vleugel M. et al.Evolution and function of the mitotic checkpoint.Dev. Cell. 2012; 23: 239-250Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar], the novel ('new') Crk6 [42Alvarez C.A. Suvorova E.S. Checkpoints of apicomplexan cell division identified in Toxoplasma gondii.PLoS Pathog. 2017; 13e1006483Crossref PubMed Scopus (40) Google Scholar, 43Ganter M. et al.Plasmodium falciparum CRK4 directs continuous rounds of DNA replication during schizogony.Nat. Microbiol. 2017; 2 (17017)Google Scholar] controls exit from mitosis.CytokinesisThe most outstanding feature of apicomplexan division is the ability to postpone cytokinesis during nuclear cycles (repeats of the S/M phases). This innovation may explain the short or absent G2 phase in Apicomplexa as well as the new centrosome/spindle complex relationship that independently controls karyokinesis and cytokinesis. Not surprisingly, this novel regulatory point is under the control of the 'new' Crk4 kinase in T. gondii [42Alvarez C.A. Suvorova E.S. Checkpoints of apicomplexan cell division identified in Toxoplasma gondii.PLoS Pathog. 2017; 13e1006483Crossref PubMed Scopus (40) Google Scholar]. Finally, assembly of the multilayered cytoskeleton unique for alveolates is regulated by a re-tooled ('new') Crk1/CycL complex distantly related to the eukaryotic Cdk11/CycL complex of transcriptional regulators [42Alvarez C.A. Suvorova E.S. Checkpoints of apicomplexan cell division identified in Toxoplasma gondii.PLoS Pathog. 2017; 13e1006483Crossref PubMed Scopus (40) Google Scholar]. The apicomplexan G1 phase may be initiated by sensing and transducing environmental signals via the activity of signaling kinases [78Brown K.M. et al.Plasma membrane association by N-acylation governs PKG function in Toxoplasma gondii.mBio. 2017; 8Crossref Scopus (80) Google Scholar, 79Lourido S. et al.Distinct signalling pathways control Toxoplasma egress and host-cell invasion.EMBO J. 2012; 31: 4524-4534Crossref PubMed Scopus (142) Google Scholar], which triggers an ordered biosynthetic cascade [39Behnke M.S. et al.Coordinated progression through two subtranscriptomes underlies the tachyzoite cycle of Toxoplasma gondii.PLoS One. 2010; 5e12354Crossref PubMed Scopus (185) Google Scholar, 80Bozdech Z. et al.The transcriptome of the intraerythrocytic developmental cycle of Plasmodium falciparum.PLoS Biol. 2003; 1: E5Crossref PubMed Scopus (1260) Google Scholar]. The G1 checkpoint mechanism is an atypical G1 kinase Crk2 in complex with a P/U-cyclin. Typical of eukaryotic G1 topology, low Crk2 activity in Toxoplasma gondii associates with G1 arrest, which is likely equivalent to eukaryotic Restriction or START-like checkpoints ('old'). Traditional immediate G1 effectors of E2F/DP-1/Rb (or SBF/Whi5) families are 'lost' in many Apicomplexa genomes and are possibly replaced ('borrowed') with the ApiAP2 family of transcriptional factors that were acquired from the red alga symbiont. Apicomplexan S phase has a DNA synthesis checkpoint that controls two processes: DNA damage is regulated by the inherited ('old') ATM kinase [81Vonlaufen N. et al.MYST family lysine acetyltransferase facilitates ataxia telangiectasia mutated (ATM) kinase-mediated DNA damage response in Toxoplasma gondii.J. Biol. Chem. 2010; 285: 11154-11161Crossref PubMed Scopus (29) Google Scholar], while licensing of DNA replication is likely regulated by the 'new' kinase Crk5 [10Naumov A. et al.The Toxoplasma centrocone houses cell cycle regulatory factors.mBio. 2017; 8Crossref PubMed Scopus (19) Google Scholar]. DNA-replication machinery operated by novel Crk5 (ORC/Mcm) is 'old' and nearly complete [9Matthews H. et al.Checks and balances? DNA replication and the cell cycle in Plasmodium.Parasit. Vectors. 2018; 11: 216Crossref PubMed Scopus (43) Google Scholar]. Surprisingly, the oldest ancestral checkpoint kinase Chk1 that connects G1, S phase and mitosis is missing in apicomplexans and chromerids along with factors from the Chk1 network, which supports the concept that coevolved complexes are preserved or lost as a unit [62de Lichtenberg U. et al.Evolution of cell cycle control: Same molecular machines, different regulation.Cell Cycle. 2007; 6: 1819-1825Crossref PubMed Scopus (27) Google Scholar]. Please note that conventional cell cycle has an additional DNA damage/replication checkpoint in the G2 phase that is likely lost in apicomplexans due to the absence of a detectable G2 period and associated regulators, such as Cdc25a phosphatase (see Figure 3 in main text). Mitosis in apicomplexan cell division has retained many 'old' components of the primordial cell cycle. Duplication and segregation of MTOC (centrosome or centrosomal plaque) that establishes spindle poles for chromosome segregation is similarly regulated by serine/threonine protein kinases of Nek and Aurora families [9Matthews H. et al.Checks and balances? DNA replication and the cell cycle in Plasmodium.Parasit. Vectors. 2018; 11: 216Crossref PubMed Scopus (43) Google Scholar, 13Suvorova E.S. et al.A novel bipartite centrosome coordinates the apicomplexan cell cycle.PLoS Biol. 2015; 13e1002093Crossref PubMed Scopus (68) Google Scholar, 34Chen C.T. Gubbels M.J. The Toxoplasma gondii centrosome is the platform for internal daughter budding as revealed by a Nek1 kinase mutant.J. Cell Sci. 2013; 126: 3344-3355Crossref PubMed Scopus (43) Google Scholar, 82Berry L. et al.The conserved apicomplexan Aurora kinase TgArk3 is involved in endodyogeny, duplication rate and parasite virulence.Cell. Microbiol. 2016; 18: 1106-1120Crossref PubMed Scopus (23) Google Scholar, 83Carvalho T.G. et al.Nima- and Aurora-related kinases of malaria parasites.Biochim. Biophys. Acta. 2013; 1834: 1336-1345Crossref PubMed Scopus (36) Google Scholar], while polo-like kinases (PLKs) are 'lost' in apicomplexans and ancestral chromerids. Similar to canonical spindle-assembly checkpoint (SAC), apicomplexan parasites regulate metaphase-to-anaphase transition. While many components of the SAC network are preserved in apicomplexans ('old': MCC – mitotic checkpoint complex, APC/C – anaphase-promoting complex/cyclosome) [72Vleugel M. et al.Evolution and function of the mitotic checkpoint.Dev. Cell. 2012; 23: 239-250Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar], the novel ('new') Crk6 [42Alvarez C.A. Suvorova E.S. Checkpoints of apicomplexan cell division identified in Toxoplasma gondii.PLoS Pathog. 2017; 13e1006483Crossref PubMed Scopus (40) Google Scholar, 43Ganter M. et al.Plasmodium falciparum CRK4 directs continuous rounds of DNA replication during schizogony.Nat. Microbiol. 2017; 2 (17017)Google Scholar] controls
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