The DNA damage response is developmentally regulated in the African trypanosome

Vieira Da Rocha, J.P., Passos-Silva, D.G., Mendes, I.C., Rocha, E.A., Gomes, D.A., Machado, C.R. and McCulloch, R. (2019) The DNA damage response is developmentally regulated in the African trypanosome. DNA Repair, 73, pp. 78-90. (doi:10.1016/j.dnarep.2018.11.005) (PMID:30470509) (PMCID:PMC6329875)

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Abstract

Genomes are affected by a wide range of damage, which has resulted in the evolution of a number of widely conserved DNA repair pathways. Most of these repair reactions have been described in the African trypanosome Trypanosoma brucei, which is a genetically tractable eukaryotic microbe and important human and animal parasite, but little work has considered how the DNA damage response operates throughout the T. brucei life cycle. Using quantitative PCR we have assessed damage induction and repair in both the nuclear and mitochondrial genomes of the parasite. We show differing kinetics of repair for three forms of DNA damage, and dramatic differences in repair between replicative life cycle forms found in the testse fly midgut and the mammal. We find that mammal-infective T. brucei cells repair oxidative and crosslink-induced DNA damage more efficiently than tsetse-infective cells and, moreover, very distinct patterns of induction and repair of DNA alkylating damage in the two life cycle forms. We also reveal robust repair of DNA lesions in the highly unusual T. brucei mitochondrial genome (the kinetoplast). By examining mutants we show that nuclear alkylation damage is repaired by the concerted action of two repair pathways, and that Rad51 acts in kinetoplast repair. Finally, we correlate repair with cell cycle arrest and cell growth, revealing that induced DNA damage has strikingly differing effects on the two life cycle stages, with distinct timing of alkylation-induced cell cycle arrest and higher levels of damage induced death in mammal-infective cells. Our data reveal that T. brucei regulates the DNA damage response during its life cycle, a capacity that may be shared by many microbial pathogens that exist in variant environments during growth and transmission.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Vieira Da Rocha, Mr Joao and Machado, Professor Carlos and Mendes, Ms Isabela and McCulloch, Professor Richard
Authors: Vieira Da Rocha, J.P., Passos-Silva, D.G., Mendes, I.C., Rocha, E.A., Gomes, D.A., Machado, C.R., and McCulloch, R.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:DNA Repair
Publisher:Elsevier
ISSN:1568-7864
ISSN (Online):1568-7856
Published Online:14 November 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in DNA Repair 73: 78-90
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 (WELLCOTR)089172/Z/09/ZIII - 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
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