Evaluation of mechanisms that may generate DNA lesions triggering antigenic variation in African trypanosomes

Santos da Silva, M., Hovel-Miner, G. A., Briggs, E. M., Elias, M. C. and McCulloch, R. (2018) Evaluation of mechanisms that may generate DNA lesions triggering antigenic variation in African trypanosomes. PLoS Pathogens, 14(11), e1007321. (doi:10.1371/journal.ppat.1007321) (PMID:30440029) (PMCID:PMC6237402)

Santos da Silva, M., Hovel-Miner, G. A., Briggs, E. M., Elias, M. C. and McCulloch, R. (2018) Evaluation of mechanisms that may generate DNA lesions triggering antigenic variation in African trypanosomes. PLoS Pathogens, 14(11), e1007321. (doi:10.1371/journal.ppat.1007321) (PMID:30440029) (PMCID:PMC6237402)

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Abstract

Antigenic variation by variant surface glycoprotein (VSG) coat switching in African trypanosomes 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:BRIGGS, Emma and McCulloch, Dr Richard and Santos Da Silva, Mr Marcelo
Authors: Santos da Silva, M., Hovel-Miner, G. A., Briggs, E. M., Elias, M. C., and McCulloch, R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN:1553-7366
ISSN (Online):1553-7374
Copyright Holders:Copyright © 2018 da Silva et al.
First Published:First published in PLoS Pathogens 14(11): e1007321
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
606431Kinase dependent control of DNA replication and repair as a drug target in Trypanosoma brucei.Richard McCullochBiotechnology and Biological Sciences Research Council (BBSRC)BB/K006495/1III - PARASITOLOGY
68706114CONFAP Understanding diverged genome repair and replication functions in trypanosomatid parasitesRichard McCullochBiotechnology and Biological Sciences Research Council (BBSRC)BB/M028909/1III - PARASITOLOGY
716221How do common and diverged features of the replicative stress response shape the biology of TriTrypRichard McCullochBiotechnology and Biological Sciences Research Council (BBSRC)BB/N016165/1III - PARASITOLOGY
515891Chromosomal recombination and repair in African trypanosomesRichard McCullochWellcome Trust (WELLCOTR)089172/Z/09/ZIII - PARASITOLOGY
3031090Challenging trypanosome antigenic variation paradigms using natural systemsRichard McCullochWellcome Trust (WELLCOTR)4251315 (206815/Z/17/Z)III - Parasitology
371799The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/Z & AIII - PARASITOLOGY