A ribosomal DNA promoter replacing the promoter of a telomeric VSG gene expression site can be efficiently switched on and off in T. brucei

Rudenko, Gloria; Blundell, Patricia A.; Dirks‐Mulder, Anita; Kieft, Rudo; Borst, Piet

doi:10.1016/0092-8674(95)90094-2

Cited by 140 publications

(131 citation statements)

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“…The very simple structure and ribosomal nature of the ES promoters (39,40) is in keeping with the absence of regulatory sequences. In support of this notion, promoters from active or inactive ESs share the same sensitivity to DNase (24), and antigenic variation still occurs properly if the promoter of the active ES is replaced by the ribosomal promoter (41,42). Other arguments include the detection of transcripts originating from inactive ESs such as RNA transcribed from the ES beginning in procyclic forms (29), RNA from antibiotic-resistance genes inserted in inactive ESs (25), or RNA from different ESAG6 from inactive ESs, accounting for up to 20% of the total ESAG6 transcripts (28).…”

Section: Discussionmentioning

confidence: 71%

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: 71%

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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“…Whether telomeric location is directly associated also with singular contingency gene expression is unclear. Where the switch between different genes proceeds by promoter activation and deactivation, such as in Plasmodium or in trypanosome transcriptional switches, TPE has been invoked (25,27,28). However, early hopes that bloodstream VSG transcriptional switching was controlled by a TPE were not well supported by further experimental analysis (57), although a modified TPE was not ruled out.…”

Section: Ku Null Mutants Do Not Have a Detectable Deficiency In Dna Dmentioning

confidence: 99%

“…Just why telomeres are so popular for such genes is unknown, but it has been speculated that the high rates of recombination between telomeres contribute to diversification within the family. It has also been proposed that telomeric location is more directly involved in phenotype switching by using effects such as TPE to enable transcriptional switching between members of the family (25,(27)(28)(29). The sleeping sickness parasite Trypanosoma brucei has a variant surface glycoprotein (VSG) protective coat that undergoes extensive antigenic variation during evasion of host immunity (reviewed in * This work was supported by the Wellcome Trust and the Royal Society.…”

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confidence: 99%

Ku Is Important for Telomere Maintenance, but Not for Differential Expression of Telomeric VSG Genes, in African Trypanosomes

Conway

McCulloch²,

Ginger³

et al. 2002

Journal of Biological Chemistry

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Trypanosome antigenic variation, involving differential expression of variant surface glycoprotein (VSG) genes, has a strong association with telomeres and with DNA recombination. All expressed VSGs are telomeric, and differential activation involves recombination into the telomeric environment or silencing/activation of subtelomeric promoters. A number of pathogen contingency gene systems associated with immune evasion involve telomeric loci, which has prompted speculation that chromosome ends provide conditions conducive for the operation of rapid gene switching mechanisms. Ku is a protein associated with eukaryotic telomeres that is directly involved in DNA recombination and in gene silencing. We have tested the hypothesis that Ku in trypanosomes is centrally involved in differential VSG expression. We show, via the generation of null mutants, that trypanosome Ku is closely involved in telomere length maintenance, more so for a transcriptionally active than an inactive telomere, but exhibits no detectable influence on DNA double strand break repair. The absence of Ku and the consequent great shortening of telomeres had no detectable influence either on the rate of VSG switching or on the silencing of the telomeric promoters of the VSG subset that is expressed in the tsetse fly.The heterodimeric protein Ku, which consists of the subunits Ku70 and Ku80 (or Ku86), associates tightly in a sequenceindependent fashion with free ends of double strand DNA and has been associated with a range of nuclear functions in different eukaryotes (reviewed in Refs.

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“…An rDNA promoter replacing the endogenous VSG expression site promoter can be switched on and off effectively (Rudenko et al 1995). In addition, different non-homologous promoters inserted into various positions in the expression site are silenced essentially equally well (Horn & Cross 1995, 1997a.…”

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confidence: 99%

Mechanisms Mediating Antigenic Variation in Trypanosoma brucei

Rudenko

1999

Mem. Inst. Oswaldo Cruz

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Antigenic variation in MECHANISMS OF ANTIGENIC VARIATIONAfrican trypanosomes are effective pathogens, as they can establish chronic infections in man and his lifestock, despite being fully exposed to periodic assault by the immune system. Their survival strategy is based on ensuring that at a low frequency, trypanosomes arise which have changed the epitopes exposed on their surface. This exchangeable surface coat is a homogeneous layer composed of a single variant surface glycoprotein (VSG). As each individual trypanosome encodes up to a thousand VSG genes, and is capable of making chimaeric new ones, the potential for variation during a protracted infection is endless.Intense research by many laboratories in the eighties laid the basis for what is known about the main mechanisms of VSG switching in bloodstream form Trypanosoma brucei. Any given VSG coat is encoded by a single VSG gene transcribed in an expression site located at the ends of certain chromosomes. As there are 20 bloodstream form VSG expression sites, one way of switching is simply to silence the active expression site and activate a new one (an in situ switch). This method of switching accesses a relatively small pool of 20 VSG genes. However, recent evidence indicates that the different VSG expression sites each con- tain genes encoding receptor proteins that are optimized for different hosts (Bitter et al. 1998). This could mean that in situ switches are important during the establishment of the trypanosome in a new host species.VSG switching can also be mediated by DNA rearrangements like gene conversions or telomere exchange. Gene conversions access the largest pool of VSG genes (virtually all of them). A silent VSG gene is copied and inserted into the active expression site, replacing the old VSG gene. Alternatively, trypanosomes can switch via telomere exchange, whereby a silent VSG gene at a chromosome end is flipped into the active VSG expression site. Recent overviews of antigenic variation are Donelson (1995), Vanhamme and Pays (1995), Borst et al. (1996), Cross (1996, Barry (1997), Rudenko et al. (1998b).The problem with studying antigenic variation in the field has been that all of these mechanisms are operating at the same time, and antigenic populations of parasites within an animal are normally not monoclonal. The 20 VSG expression sites are highly similar with each other, with only the VSG gene as a unique marker. Once the VSG gene has been switched a few times, it can be very difficult to reconstruct how this has happened. Due to the polyclonal nature of the infection, it is also impossible to prove that trypanosomes present in various peaks are sequentially derived from each other. In contrast, single relapse experiments with laboratory strains are a highly simplified model system, which should give us insights into how antigenic variation is mediated in field strains.

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A ribosomal DNA promoter replacing the promoter of a telomeric VSG gene expression site can be efficiently switched on and off in T. brucei

Cited by 140 publications

References 38 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

Ku Is Important for Telomere Maintenance, but Not for Differential Expression of Telomeric VSG Genes, in African Trypanosomes

Mechanisms Mediating Antigenic Variation in Trypanosoma brucei

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