Identification of ORC1/CDC6-Interacting Factors in Trypanosoma brucei Reveals Critical Features of Origin Recognition Complex Architecture

Tiengwe, Calvin; Marcello, Lucio; Farr, Helen; Gadelha, Catarina; Burchmore, Richard; Barry, J. David; Bell, Stephen D.; McCulloch, Richard

doi:10.1371/journal.pone.0032674

Cited by 48 publications

(98 citation statements)

References 76 publications

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“…The precise underlying molecular mechanism is still not understood. Although several molecular players have been shown to be involved (8,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), depletion of any of these factors had only a moderate effect on the repression of silent VSG genes. Therefore, either a master regulator is still to be discovered or, alternatively, the process is controlled by multiple collaborative factors ensuring a cumulative tight lock.…”

Section: Discussionmentioning

confidence: 96%

“…The mechanism controlling the selective activity of a single ES at a time is still unknown, although several factors have been found to be involved, such as differential chromatin/histone acetylation and methylation between active and inactive ESs (6-8); nucleosome depletion in the active ES (9,10); and the influence of various negative transcription modulators such as a histone methylase, a high-mobility group protein, histone H1, NLP (a nucleoplasm-like protein), a FACT subunit (a chromatin remodeler), a SWI/SNF (a chromatin remodeling factor), ORC1 and MCM-BP (proteins involved in the initiation of DNA replication), RAP1 (a telomere-binding protein), histone chaperones, or a lamin-like protein (8,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). However, no master ES regulator has been identified so far.…”

mentioning

confidence: 99%

“…Furthermore, the level at which the control takes place is unknown: Whether the transcription control takes place at the initiation or elongation level is debated. Data reporting low levels of transcripts from silent ESs upon RNAi-mediated knockdown of various factors (8,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) cannot resolve this issue, because the data are compatible with both models. Previous experiments pointed to mixed conclusions.…”

mentioning

confidence: 99%

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Transcription is initiated on silent variant surface glycoprotein expression sites despite monoallelic expression in Trypanosoma brucei

Kassem

Pays

Vanhamme

2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance African trypanosomes are a major plague in sub-Saharan Africa. They cause sleeping sickness in humans and nagana in cattle, preventing extensive cattle raising. They escape the immune system of their host through frequent changes in their major surface antigen, the variant surface glycoprotein (VSG). The control of VSG expression is poorly understood, and the level at which it takes place has been a matter of debate for the last 25 y. A better understanding of the mechanism by which it works would facilitate the identification of the proteins involved and would provide putative targets for drug design. We report data indicating an unusual control level, namely after transcription initiation, suggesting transcription elongation or RNA processing as a control step.

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Section: Discussionmentioning

confidence: 96%

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confidence: 99%

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confidence: 99%

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Transcription is initiated on silent variant surface glycoprotein expression sites despite monoallelic expression in Trypanosoma brucei

Kassem

Pays

Vanhamme

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Also note that only one DNA polymerase is depicted here, for the sake of simplicity. distantly related to Orc4 and the other two (Tb3120 and Tb7980) have little sequence homology to known ORC proteins (107). The tight association of TbOrc1/Cdc6 with the chromatin throughout the cell cycle strongly suggests its role as a component of the ORC, rather than as the licensing factor Cdc6, which is known to be either degraded (in fungi) or exported out of the nucleus (in metazoa) after DNA replication.…”

Section: Dna Replication Licensing and Regulation Of S-phase Progressionmentioning

confidence: 99%

“…These findings suggest that trypanosomes have evolved distinct mechanisms in promoting DNA replication initiation and preventing DNA rereplication. Based on our current understanding of DNA replication initiation in other eukaryotes (26) and the identification of the above-mentioned protein complexes in trypanosomes (20,35,107), we propose a model of DNA replication in trypanosomes (Fig. 1B).…”

Section: Dna Replication Licensing and Regulation Of S-phase Progressionmentioning

confidence: 99%

Regulation of the Cell Division Cycle in Trypanosoma brucei

Li¹

2012

Eukaryot Cell

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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.

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A Host–Pathogen Interaction Reduced to First Principles: Antigenic Variation in T. brucei

Hovel-Miner

Mugnier

Papavasiliou

et al. 2015

Results and Problems in Cell Differentiation

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Antigenic variation is a common microbial survival strategy, powered by diversity in expressed surface antigens across the pathogen population over the course of infection. Even so, among pathogens, African trypanosomes have the most comprehensive system of antigenic variation described. African trypanosomes (Trypanosoma brucei spp.) are unicellular parasites native to sub-Saharan Africa, and the causative agents of sleeping sickness in humans and of n'agana in livestock. They cycle between two habitats: a specific species of fly (Glossina spp. or, colloquially, the tsetse) and the bloodstream of their mammalian hosts, by assuming a succession of proliferative and quiescent developmental forms, which vary widely in cell architecture and function. Key to each of the developmental forms that arise during these transitions is the composition of the surface coat that covers the plasma membrane. The trypanosome surface coat is extremely dense, covered by millions of repeats of developmentally specified proteins: procyclin gene products cover the organism while it resides in the tsetse and metacyclic gene products cover it while in the fly salivary glands, ready to make the transition to the mammalian bloodstream. But by far the most interesting coat is the Variant Surface Glycoprotein (VSG) coat that covers the organism in its infectious form (during which it must survive free living in the mammalian bloodstream). This coat is highly antigenic and elicits robust VSG-specific antibodies that mediate efficient opsonization and complement mediated lysis of the parasites carrying the coat against which the response was made. Meanwhile, a small proportion of the parasite population switches coats, which stimulates a new antibody response to the prevalent (new) VSG species and this process repeats until immune system failure. The disease is fatal unless treated, and treatment at the later stages is extremely toxic. Because the organism is free living in the blood, the VSG:antibody surface represents the interface between pathogen and host, and defines the interaction of the parasite with the immune response. This interaction (cycles of VSG switching, antibody generation, and parasite deletion) results in stereotypical peaks and troughs of parasitemia that were first recognized more than 100 years ago. Essentially, the mechanism of antigenic variation in T. brucei results from a need, at the population level, to maintain an extensive repertoire, to evade the antibody response. In this chapter, we will examine what is currently known about the VSG repertoire, its depth, and the mechanisms that diversify it both at the molecular (DNA) and at the phenotypic (surface displayed) level, as well as how it could interact with antibodies raised specifically against it in the host.

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Identification of ORC1/CDC6-Interacting Factors in Trypanosoma brucei Reveals Critical Features of Origin Recognition Complex Architecture

Cited by 48 publications

References 76 publications

Transcription is initiated on silent variant surface glycoprotein expression sites despite monoallelic expression in Trypanosoma brucei

Transcription is initiated on silent variant surface glycoprotein expression sites despite monoallelic expression in Trypanosoma brucei

Regulation of the Cell Division Cycle in Trypanosoma brucei

A Host–Pathogen Interaction Reduced to First Principles: Antigenic Variation in T. brucei

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