| Full text | |
| Author(s): |
da Silva, Marcelo Santos
[1, 2]
;
Hovel-Miner, Galadriel A.
[3]
;
Briggs, Emma M.
[1]
;
Elias, Maria Carolina
[2]
;
Mcculloch, Richard
[1]
Total Authors: 5
|
| Affiliation: | [1] Univ Glasgow, Inst Infect Immun & Inflammat, Wellcome Ctr Mol Parasitol, Glasgow, Lanark - Scotland
[2] Inst Butantan, Ctr Toxins Immune Response & Cell Signaling CeTIC, Lab Especial Ciclo Celular, Sao Paulo - Brazil
[3] George Washington Univ, Dept microbiol Immunol & Trop Med, Washington, DC - USA
Total Affiliations: 3
|
| Document type: | Review article |
| Source: | PLOS PATHOGENS; v. 14, n. 11 NOV 2018. |
| Web of Science Citations: | 4 |
| Abstract | |
Antigenic variation by variant surface glycoprotein (VSG) coat switching in African trypano-somes is one of the most elaborate immune evasion strategies found among pathogens. Changes in the identity of the transcribed VSG gene, which is always flanked by 70-bp and telomeric repeats, can be achieved either by transcriptional or DNA recombination mechanisms. The major route of VSG switching is DNA recombination, which occurs in the bloodstream VSG expression site (ES), a multigenic site transcribed by RNA polymerase I. Recombinogenic VSG switching is frequently catalyzed by homologous recombination (HR), a reaction normally triggered by DNA breaks. However, a clear understanding of how such breaks arise-including whether there is a dedicated and ES-focused mechanism-is lacking. Here, we synthesize data emerging from recent studies that have proposed a range of mechanisms that could generate these breaks: action of a nuclease or nucleases; repetitive DNA, most notably the 70-bp repeats, providing an intra-ES source of instability; DNA breaks derived from the VSG-adjacent telomere; DNA breaks arising from high transcription levels at the active ES; and DNA lesions arising from replication-transcription conflicts in the ES. We discuss the evidence that underpins these switch-initiation models and consider what features and mechanisms might be shared or might allow the models to be tested further. Evaluation of all these models highlights that we still have much to learn about the earliest acting step in VSG switching, which may have the greatest potential for therapeutic intervention in order to undermine the key reaction used by trypanosomes for their survival and propagation in the mammalian host. (AU) | |
| FAPESP's process: | 13/07467-1 - CeTICS - Center of Toxins, Immune-Response and Cell Signaling |
| Grantee: | Hugo Aguirre Armelin |
| Support Opportunities: | Research Grants - Research, Innovation and Dissemination Centers - RIDC |
| FAPESP's process: | 14/24170-5 - DNA replication dynamics in Trypanosoma cruzi: licensing and replication rate characterization |
| Grantee: | Marcelo Santos da Silva |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |
| FAPESP's process: | 17/18719-2 - Structural analysis of the origin recognition complex (ORC) in Trypanosoma brucei using cryo-electron microscopy and single-particle analysis |
| Grantee: | Marcelo Santos da Silva |
| Support Opportunities: | Scholarships abroad - Research Internship - Post-doctor |
| FAPESP's process: | 16/50050-2 - How do common and diverged features of the replicative stress response shape the biology of TriTryp parasites? |
| Grantee: | Maria Carolina Quartim Barbosa Elias Sabbaga |
| Support Opportunities: | Research Projects - Thematic Grants |