RAP1 Is Essential for Silencing Telomeric Variant Surface Glycoprotein Genes in Trypanosoma brucei

Yang, Xiaofeng; Figueiredo, Luísa M.; Espinal, Amin; Okubo, Eiji; Li, Bibo

doi:10.1016/j.cell.2009.01.037

Cited by 158 publications

(431 citation statements)

References 68 publications

Supporting

Mentioning

397

Contrasting

Unclassified

Order By: Relevance

“…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: 83%

“…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%

See 1 more Smart Citation

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.

View full text Add to dashboard Cite

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.

show abstract

mentioning

confidence: 83%

mentioning

confidence: 99%

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.

View full text Add to dashboard Cite

show abstract

“…The telomere complex has been shown to play an important role in T. brucei pathogenesis [31]. Therefore, altering the TbTR template sequence can have a profound effect on the telomere structure, which may have therapeutic implications.…”

Section: Discussionmentioning

confidence: 99%

“…Particularly, T. brucei telomere sequence [34] and T-loop structure [35,36] are identical to those in humans, and the telomere protein complex is largely conserved between T. brucei and vertebrates [31,37]. Therefore, T. brucei can serve as a useful model system for dissecting the structure and function of telomerase in pathogenic protozoa and for comparative analysis of telomerase function and evolution in general.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, when the active VSG-marked telomere is shortened to ~1 kb, the VSG switching rate is increased by ~10-fold [30]. In addition, TbRAP1, an intrinsic T. brucei telomere component, is essential for regulation of subtelomeric VSG gene expression [31]. Therefore, understanding the telomerase-mediated telomere maintenance in T. brucei can help to elucidate the mechanisms of T. brucei pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A trans-spliced telomerase RNA dictates telomere synthesis in Trypanosoma brucei

et al. 2013

Self Cite

View full text Add to dashboard Cite

Telomerase is a ribonucleoprotein enzyme typically required for sustained cell proliferation. Although both telomerase activity and the telomerase catalytic protein component, TbTERT, have been identified in the eukaryotic pathogen Trypanosoma brucei, the RNA molecule that dictates telomere synthesis remains unknown. Here, we identify the RNA component of Trypanosoma brucei telomerase, TbTR, and provide phylogenetic and in vivo evidence for TbTR's native folding and activity. We show that TbTR is processed through trans-splicing, and is a capped transcript that interacts and copurifies with TbTERT in vivo. Deletion of TbTR caused progressive shortening of telomeres at a rate of 3-5 bp/population doubling (PD), which can be rescued by ectopic expression of a wild-type allele of TbTR in an apparent dose-dependent manner. Remarkably, introduction of mutations in the TbTR template domain resulted in corresponding mutant telomere sequences, demonstrating that telomere synthesis in T. brucei is dependent on TbTR. We also propose a secondary structure model for TbTR based on phylogenetic analysis and chemical probing experiments, thus defining TbTR domains that may have important functional implications in telomere synthesis. Identification and characterization of TbTR not only provide important insights into T. brucei telomere functions, which have been shown to play important roles in T. brucei pathogenesis, but also offer T. brucei as an attractive model system for studying telomerase biology in pathogenic protozoa and for comparative analysis of telomerase function with higher eukaryotes.

show abstract

Telomerase ribonucleoprotein and genome integrity—An emerging connection in protozoan parasites

Davis

Chakrabarti

2021

WIREs RNA

View full text Add to dashboard Cite

Telomerase has an established role in telomere maintenance in eukaryotes. However, recent studies have begun to implicate telomerase in cellular roles beyond telomere maintenance. Specifically, evidence is emerging of cross‐talks between telomerase mediated telomere homeostasis and DNA repair pathways. Telomere shortening due to the end replication problem is a constant threat to genome integrity in eukaryotic cells. This poses a particular problem in unicellular parasitic protists because their major virulence genes are located at the subtelomeric loci. Although telomerase is the major regulator of telomere lengthening in eukaryotes, it is less studied in the ancient eukaryotes, including clinically important human pathogens. Recent research is highlighting interplay between telomerase and the DNA damage response in human parasites. The importance of this interplay in pathogen virulence is only beginning to be illuminated, including the potential to highlight novel developmental regulation of telomerase in parasites who transition between multiple developmental stages throughout their life cycle. In this review, we will discuss the telomerase ribonucleoprotein enzyme and DNA repair pathways with emerging views in human parasites to give a broader perspective of the possible connection of telomere, telomerase, and DNA repair pathways across eukaryotic lineages and highlight their potential role in pathogen virulence. This article is categorized under: RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications

show abstract

RAP1 Is Essential for Silencing Telomeric Variant Surface Glycoprotein Genes in Trypanosoma brucei

Cited by 158 publications

References 68 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

A trans-spliced telomerase RNA dictates telomere synthesis in Trypanosoma brucei

Telomerase ribonucleoprotein and genome integrity—An emerging connection in protozoan parasites

Contact Info

Product

Resources

About