Abstract
Survival of Trypanosoma brucei depends upon switches in its protective Variant Surface Glycoprotein (VSG) coat by antigenic variation. VSG switching occurs by frequent homologous recombination, which is thought to require locus-specific initiation. Here, we show that a RecQ helicase, RECQ2, acts to repair DNA breaks, including in the telomeric site of VSG expression. Despite this, RECQ2 loss does not impair antigenic variation, but causes increased VSG switching by recombination, arguing against models for VSG switch initiation through direct generation of a DNA double strand break (DSB). Indeed, we show DSBs inefficiently direct recombination in the VSG expression site. By mapping genome replication dynamics, we reveal that the transcribed VSG expression site is the only telomeric site that is early replicating - a differential timing only seen in mammal-infective parasites. Specific association between VSG transcription and replication timing reveals a model for antigenic variation based on replication-derived DNA fragility.
Highlights
The growth and propagation of pathogens in vertebrates requires strategies to survive the host immune responses, in particular adaptive immunity
Understanding the initiation event(s) of Variant Surface Glycoprotein (VSG) switching by recombination is important, since this element of the reaction may be lineage-specific, and might explain both the elevated rate of the reaction relative to general homologous recombination (HR) and the potential focus on the active bloodstream expression sites (BES)
VSG switch initiation has been modelled by the direct generation of a double strand break (DSB) in the active BES through the controlled expression and targeting of I-SceI (Boothroyd et al, 2009; Glover et al, 2013; Glover and Horn, 2014), which results in VSG switching
Summary
The growth and propagation of pathogens in vertebrates requires strategies to survive the host immune responses, in particular adaptive immunity. At any given time an individual T. brucei cell in the mammal expresses only one VSG gene, due to transcriptional control mechanisms that ensure only one of ~15 VSG transcription sites, termed bloodstream expression sites (BES), is active. Such monoallelic expression is found in other antigenic variation systems, such as that involving the ~60 var genes in Plasmodium falciparum (Guizetti and Scherf, 2013), as is the ability to switch the gene that is actively transcribed, eliciting antigenic variation.
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