Mapping replication dynamics in Trypanosoma brucei reveals a link with telomere transcription and antigenic variation

Devlin, R., Marques, C. A. , Paape, D. , Prorocic, M., Zurita-Leal, A. C., Campbell, S. J., Lapsley, C., Dickens, N. and McCulloch, R. (2016) Mapping replication dynamics in Trypanosoma brucei reveals a link with telomere transcription and antigenic variation. eLife, 5, e12765. (doi: 10.7554/eLife.12765) (PMID:27228154) (PMCID:PMC4946898)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Paape, Dr Daniel and De Almeida Marques, Dr Catarina and Dickens, Dr Nicholas and Lapsley, Mr Craig and McCulloch, Professor Richard and Prorocic, Dr Marko
Authors: Devlin, R., Marques, C. A., Paape, D., Prorocic, M., Zurita-Leal, A. C., Campbell, S. J., Lapsley, C., Dickens, N., and McCulloch, R.
Subjects:Q Science > Q Science (General)
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:eLife
Publisher:eLife Sciences Publications
ISSN:2050-084X
ISSN (Online):2050-084X
Copyright Holders:Copyright © 2016 Devlin et al.
First Published:First published in eLife 5: e12765
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
515891Chromosomal recombination and repair in African trypanosomesRichard McCullochWellcome Trust (WELLCOME)089172/Z/09/ZIII - PARASITOLOGY
371799The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOME)104111/Z/14/Z &III - PARASITOLOGY
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
558544Do DNA double strand breaks initiate antigenic variation by homologous recombination in Trypanossoma brucei?Richard McCullochWellcome Trust (WELLCOME)093589/Z/10/BIII - PARASITOLOGY