Trypanosoma brucei ATR links DNA damage signalling during antigenic variation with regulation of RNA Polymerase I-transcribed surface antigens

Black, J. A., Crouch, K. , Lemgruber, L., Lapsley, C., Dickens, N. , Tosi, L. R.O., Mottram, J. C. and McCulloch, R. (2020) Trypanosoma brucei ATR links DNA damage signalling during antigenic variation with regulation of RNA Polymerase I-transcribed surface antigens. Cell Reports, 30(3), 836-851.e5. (doi: 10.1016/j.celrep.2019.12.049) (PMID:31968257) (PMCID:PMC6988115)

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Abstract

Trypanosoma brucei evades mammalian immunity by using recombination to switch its surface-expressed variant surface glycoprotein (VSG), while ensuring that only one of many subtelomeric multigene VSG expression sites are transcribed at a time. DNA repair activities have been implicated in the catalysis of VSG switching by recombination, not transcriptional control. How VSG switching is signaled to guide the appropriate reaction or to integrate switching into parasite growth is unknown. Here, we show that the loss of ATR, a DNA damage-signaling protein kinase, is lethal, causing nuclear genome instability and increased VSG switching through VSG-localized damage. Furthermore, ATR loss leads to the increased transcription of silent VSG expression sites and expression of mixed VSGs on the cell surface, effects that are associated with the altered localization of RNA polymerase I and VEX1. This work shows that ATR acts in antigenic variation both through DNA damage signaling and surface antigen expression control.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Black, Dr Jennifer and Lapsley, Mr Craig and McCulloch, Professor Richard and Mottram, Professor Jeremy and Dickens, Dr Nicholas and Crouch, Dr Kathryn and Lemgruber Soares, Dr Leandro
Authors: Black, J. A., Crouch, K., Lemgruber, L., Lapsley, C., Dickens, N., Tosi, L. R.O., Mottram, J. C., and McCulloch, R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Cell Reports
Publisher:Elsevier
ISSN:2211-1247
ISSN (Online):2211-1247
Published Online:21 January 2020
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Cell Reports 30(3):836-851.e5
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
167605Kinase 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
17115214CONFAP Understanding diverged genome repair and replication functions in trypanosomatid parasitesRichard McCullochBiotechnology and Biological Sciences Research Council (BBSRC)BB/M028909/1III - Parasitology
173173How 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
171824Characterization of Toxoplasma gondii interaction with the human host cell and Host-Parasite co-evolution: Toxoplasma gondii as a case studyMusa HassanWellcome Trust (WELLCOTR)104111/B/14/ZIII - Parasitology