Ribonuclease H1-targeted R-loops in surface antigen gene expression sites can direct trypanosome immune evasion

Briggs, E., Crouch, K. , Lemgruber, L., Lapsley, C. and McCulloch, R. (2018) Ribonuclease H1-targeted R-loops in surface antigen gene expression sites can direct trypanosome immune evasion. PLoS Genetics, 14(12), e1007729. (doi:10.1371/journal.pgen.1007729) (PMID:30543624) (PMCID:PMC6292569)

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Abstract

Switching of the Variant Surface Glycoprotein (VSG) in Trypanosoma brucei provides a crucial host immune evasion strategy that is catalysed both by transcription and recombination reactions, each operating within specialised telomeric VSG expression sites (ES). VSG switching is likely triggered by events focused on the single actively transcribed ES, from a repertoire of around 15, but the nature of such events is unclear. Here we show that RNA-DNA hybrids, called R-loops, form preferentially within sequences termed the 70 bp repeats in the actively transcribed ES, but spread throughout the active and inactive ES, in the absence of RNase H1, which degrades R-loops. Loss of RNase H1 also leads to increased levels of VSG coat switching and replication-associated genome damage, some of which accumulates within the active ES. This work indicates VSG ES architecture elicits R-loop formation, and that these RNA-DNA hybrids connect T. brucei immune evasion by transcription and recombination.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Lapsley, Mr Craig and Briggs, Miss Emma and McCulloch, Professor Richard and Crouch, Dr Kathryn and Lemgruber Soares, Dr Leandro
Creator Roles:
Briggs, E.Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review and editing
Crouch, K.Data curation, Formal analysis, Investigation, Methodology, Software, Validation, Visualization, Writing – original draft, Writing – review and editing
Lemgruber, L.Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – review and editing
Lapsley, C.Investigation, Methodology, Validation
McCulloch, R.Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Writing – original draft, Writing – review and editing
Authors: Briggs, E., Crouch, K., Lemgruber, L., Lapsley, C., and McCulloch, R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Genetics
Publisher:Public Library of Science
ISSN:1553-7390
ISSN (Online):1553-7404
Copyright Holders:Copyright © 2018 Briggs et al.
First Published:First published in PLoS Genetics 14(12): e1007729
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
371799The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/Z & AIII - PARASITOLOGY