ArticlePLoS pathogens2013
DNA break site at fragile subtelomeres determines probability and mechanism of antigenic variation in African trypanosomes.
Article in PLoS pathogens, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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Who cites it
76 citing papers in PubMed, 107 citations in OpenAlex.
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- Insight into the epigenetic regulation of gene expression in the bloodstream and procyclic forms ofNAR genomics and bioinformatics · 2025Article
- Next generation genetic screens in kinetoplastids.Nucleic acids research · 2025Review
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- TelAP2 links TelAP1 to the telomere complex in Trypanosoma brucei.Scientific reports · 2024Article
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- Unwrap RAP1's Mystery at Kinetoplastid Telomeres.Biomolecules · 2024Review
- Identifying Antigenic Switching by Clonal Cell Barcoding and Nanopore Sequencing inBio-protocol · 2023Article
- RAD51-mediated R-loop formation acts to repair transcription-associated DNA breaks driving antigenic variation inProceedings of the National Academy of Sciences of the United States of America · 2023Article
- Immunoprecipitation of RNA-DNA hybrid interacting proteins in Trypanosoma brucei reveals conserved and novel activities, including in the control of surface antigen expression needed for immune evasion by antigenic variation.Nucleic acids research · 2023Article
- Decoding the impact of nuclear organization on antigenic variation in parasites.Nature microbiology · 2023Review
- Identification of a small-molecule inhibitor that selectively blocks DNA-binding by Trypanosoma brucei replication protein A1.Nature communications · 2023Article
- Competition among variants is predictable and contributes to the antigenic variation dynamics of African trypanosomes.PLoS pathogens · 2023Article
- G-Quadruplexes as Key Transcriptional Regulators in Neglected Trypanosomatid Parasites.Chembiochem : a European journal of chemical biology · 2023Review
- The RRM-mediated RNA binding activity in T. brucei RAP1 is essential for VSG monoallelic expression.Nature communications · 2023Article
- Telomere maintenance in African trypanosomes.Frontiers in molecular biosciences · 2023Review
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- POLIE suppresses telomerase-mediated telomere G-strand extension and helps ensure proper telomere C-strand synthesis in trypanosomes.Nucleic acids research · 2022Article
16 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Antigenic variation in African trypanosomes requires monoallelic transcription and switching of variant surface glycoprotein (VSG) genes. The transcribed VSG, always flanked by '70 bp'-repeats and telomeric-repeats, is either replaced through DNA double-strand break (DSB) repair or transcriptionally inactivated. However, little is known about the subtelomeric DSBs that naturally trigger antigenic variation in Trypanosoma brucei, the subsequent DNA damage responses, or how these responses determine the mechanism of VSG switching. We found that DSBs naturally accumulate close to both transcribed and non-transcribed telomeres. We then induced high-efficiency meganuclease-mediated DSBs and monitored DSB-responses and DSB-survivors. By inducing breaks at distinct sites within both transcribed and silent VSG transcription units and assessing local DNA resection, histone modification, G2/M-checkpoint activation, and both RAD51-dependent and independent repair, we reveal how breaks at different sites trigger distinct responses and, in 'active-site' survivors, different switching mechanisms. At the active site, we find that promoter-adjacent breaks typically failed to trigger switching, 70 bp-repeat-adjacent breaks almost always triggered switching through 70 bp-repeat recombination (∼60% RAD51-dependent), and telomere-repeat-adjacent breaks triggered switching through loss of the VSG expression site (25% of survivors). Expression site loss was associated with G2/M-checkpoint bypass, while 70 bp-repeat-recombination was associated with DNA-resection, γH2A-focus assembly and a G2/M-checkpoint. Thus, the probability and mechanism of antigenic switching are highly dependent upon the location of the break. We conclude that 70 bp-repeat-adjacent and telomere-repeat-adjacent breaks trigger distinct checkpoint responses and VSG switching pathways. Our results show how subtelomere fragility can generate the triggers for the major antigenic variation mechanisms in the African trypanosome.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.