Regulation of the Cell Division Cycle in Trypanosoma brucei

Abstract

The cell division cycle is tightly regulated by the activation and inactivation of a series of proteins that control the replication and segregation of organelles to the daughter cells. During the past decade, we have witnessed significant advances in our understanding of the cell cycle in Trypanosoma brucei and how the cycle is regulated by various regulatory proteins. However, many other regulators, especially those unique to trypanosomes, remain to be identified, and we are just beginning to delineate the signaling pathways that drive the transitions through different cell cycle stages, such as the G 1 /S transition, G 2 /M transition, and mitosis-cytokinesis transition. Trypanosomes appear to employ both evolutionarily conserved and trypanosome-specific molecules to regulate the various stages of its cell cycle, including DNA replication initiation, spindle assembly, chromosome segregation, and cytokinesis initiation and completion. Strikingly, trypanosomes lack some crucial regulators that are well conserved across evolution, such as Cdc6 and Cdt1, which are involved in DNA replication licensing, the spindle motor kinesin-5, which is required for spindle assembly, the central spindlin complex, which has been implicated in cytokinesis initiation, and the actomyosin contractile ring, which is located at the cleavage furrow. Conversely, trypanosomes possess certain regulators, such as cyclins, cyclin-dependent kinases, and mitotic centromere-associated kinesins, that are greatly expanded and likely play diverse cellular functions. Overall, trypanosomes apparently have integrated unique regulators into the evolutionarily conserved pathways to compensate for the absence of those conserved molecules and, additionally, have evolved certain cell cycle regulatory pathways that are either different from its human host or distinct between its own life cycle forms.

Two distinct cytokinesis pathways drive trypanosome cell division initiation from opposite cell ends

“…Trypanosomes initiate cytokinesis from the anterior tip of the new FAZ filament, and it is believed that the regulators playing direct roles in cytokinesis initiation should localize to the new FAZ tip before cytokinesis initiation (21). CIF1 is the fifth protein, after TbAUK1 (12), TbCPC1 (12), TbCPC2 (12), and TbPLK (22), that concentrates at the new FAZ tip, and our RNAi studies demonstrated that CIF1 is essential for cytokinesis initiation from the anterior tip of the new FAZ filament (Fig.…”

Trypanosome cdc2-Related Kinase 9 Controls Spliced Leader RNA cap4 Methylation and Phosphorylation of RNA Polymerase II Subunit RPB1

“…Fourthly, cyclin-dependent kinases in general are considered to be among the most promising drug targets, due to their key function in cell proliferation (61). Accordingly, CRK9 silencing has been shown to affect trypanosome mitosis and cytokinesis (42,62).…”

The Neomuran Revolution and Phagotrophic Origin of Eukaryotes and Cilia in the Light of Intracellular Coevolution and a Revised Tree of Life

“…Ancestral eukaryotes evolved origin recognition complexes (ORCs) more complex than the single protein Cdc-6 of archaebacteria, probably because the suddenness of mitotic anaphase (rapidly segregating all parts of chromosomes at once, unlike the temporally separate segregation of origins and the generally single terminus in bacteria) required concerted replication initiation at hundreds of origins, ensuring replication completion and tighter chromosome folding (using extra histones and novel heterochromatin machinery: Cavalier-Smith 2010c) well before mitosis; uniquely in eukaryotes, mitosis demands a temporally discrete S phase. Formerly, only neokaryotes were thought to have ORCs (Cavalier-Smith 2010b), but extremely divergent versions of most constituents are now known in trypanosomes, whose cell-cycle controls are the most divergent within eukaryotes (Li 2012), consistent with eukaryotic rooting between Euglenozoa and neokaryotes ( Figs. 1 and 3).…”

“…Successively more complex controls and checkpoints evolved with novel polo-like and aurora S/T kinases playing multifarious roles in mitosis and cytokinesis and a multiplicity of kinesins evolving to improve spindle assembly and function. Probably all proteins shared by trypanosomes (Li 2012) and opisthokonts evolved before the eukaryote cenancestor. Mitosis (upper panel) was converted to meiosis by two innovations (lower panel): homologous chromosome pairing by the synaptonemal complex and blocking centromeric cohesin digestion at meiosis 1 anaphase, which automatically bypassed cell-cycle resetting caused by anaphase centromere splitting so that the next interphase had no S phase as previously explained (Cavalier-Smith 1981), thereby halving ploidy-the original meiotic function (Cavalier-Smith 2002a, 2010c.…”